Telmisartan , Micardis is a well known angiotensin II receptor antagonist used in the treatment of hypertension and, heart and bladder diseases. As shown previously, such benzimidazoles can be formed through the condensation reaction of a 1,2-diaminobenzene and a suitable functionalised carbonyl compound. However, in the case of telmisartan other inherent functionalities such as an ester are present which leads to the formation of several by-products and consequently significantly lower yields.
Scheme Medicinal chemistry route to telmisartan. Hence an improved synthesis was sought . This revised route utilised a palladium-mediated reduction of the highly substituted nitrobenzene derivative to afford aniline which under basic conditions ring closes to the corresponding benzimidazole Under the same reaction conditions, the hydrolysis of the methyl ester also occurs which allows the introduction of the second imidazole group in the subsequent condensation step.
Scheme Improved synthesis of telmisartan. Zolpidem is a non-benzodiazepine hypnotic, and is part of the imidazopyridine class of pharmaceuticals. Zolpidem binds to GABA receptors at the same site as typical benzodiazepines. This drug is preferred to benzodiazepines for long term use since benzodiazepines lead to a higher tolerance as well as physical dependence. Scheme Synthesis of zolpidem.
In a recent study a more straightforward and general copper-catalysed three component coupling leading to imidazopyridines has been reported . For this reaction 2-aminomethylpyridine was condensed with an aldehyde to form an intermediate imine to which is added a terminal alkyne in the presence of copper I chloride. Scheme Copper-catalysed 3-component coupling towards zolpidem. Despite this synthesis being much shorter and convergent it has some limitations since the entire procedure needs to be performed in a glove box and has consequently only been reported on small scale.
Selective inhibitors of cyclooxygenase-2 COX-2 are widely used for their anti-inflammatory effects and have shown less gastrointestinal side effects when compared to other anti-inflammatory agents, notably non-steroidal anti-inflammatory drugs NSAIDs such as aspirin and ibuprofen, which inhibit both COX-1 and COX The central ring is usually a five-membered aromatic system, which is diaryl-substituted with a Z -stilbene-like linking structure.
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A polar sulfonamide group or biologically equivalent unit is usually present at the para -position of one of the aryl rings and is believed to promote binding to a hydrophilic pocket close to the active site of COX Interestingly, celecoxib has also been approved for familial adenomatous polyposis demonstrating its ability to induce apoptosis in certain cancer cell lines .
As this activity is not shared with all COX-2 inhibitors, it is believed that the structural features such as the polar sulfonamide group, the lipophilic tolyl moiety and the trifluoromethylated pyrazole core with its negative electrostatic potential play a key role in apoptosis induction.
Consequently, the anti-inflammatory and apoptosis inducing properties of celecoxib are assumed to result via different modes of action. Figure 7: Structure of celecoxib.
In a recent study  , celecoxib has also been shown to be a rapid, freely reversible, competitive inhibitor of COX This result was supported by X-ray crystallographic evidence, where celecoxib was shown to bind to one subunit of the COXdimer, implying that drugs like aspirin then bind to the other monomer of the same enzyme consequently slowing down the irreversible acetylation of a serine residue by aspirin itself.
This finding is relevant as aspirin is clinically used in combination with celecoxib to attenuate its cardiovascular side effects. Based on this in vitro study, it is suggested that the cardioprotective effects of low-dose aspirin on COX-1 might be reduced when administered with celecoxib. Further studies are currently underway to elucidate the full sympathetic action of co-administration. Scheme Preparation of celecoxib. The immediate downside to this approach is the generation of regioisomeric mixtures.
However, this is often of minor concern. Alternatively, in order to circumvent the regioselectivity issue, other pyrazole syntheses have been used. For example, the substituted aryl hydrazine can be reacted with trifluoromethyl butynone in a one pot reaction. Scheme Alternative synthesis of celecoxib. A novel 1,3-dipolar cycloaddition between a nitrile imide and an appropriately substituted olefin has also been used to obtain the corresponding trisubstituted pyrazole . Scheme Regioselective access to celecoxib. This high regioselectivity is only obtained when a 1,1-disubstituted enamine is used, the corresponding 1,2-disubstituted enamine yields mainly the other regioisomer.
Pazopanib , Votrient is a new potent multi-target tyrosine kinase inhibitor for various human cancer cell lines. Pazopanib is considered a promising replacement treatment to imatinib and sunitinib and was approved for renal cell carcinoma by the FDA in late The indazole system is built up via diazotisation and spontaneous cyclisation of 2-ethylnitroaniline using tert -butyl nitrite.
A tin-mediated reduction of the nitro group unmasks the aniline which undergoes nucleophilic aromatic substitution to introduce the pyrimidine system with the formation of Scheme Synthesis of pazopanib. Although many common antifungal drugs contain at least one 1,2,4-triazole ring, barely any of these drugs are represented in the top drugs based on the value of sales. This observation obviously reflects more the price differential of the drug class rather than the utility of the heterocycle.
In general, the triazole containing drugs belong to two groups of therapeutic agents: selective and non-steroidal aromatase inhibitors which are used in the treatment of early and advanced breast cancer in postmenopausal women, e. Scheme Syntheses of anastrozole, rizatriptan and letrozole. In order to circumvent the formation of the undesired regioisomer, a strategy that is often used is to react the corresponding benzyl bromide component first with 4-amino-1,2,4-triazole to form a quaternary ammonium salt.
Scheme Regioselective synthesis of anastrozole. Other synthetic routes to 1,2,4-triazoles have also been reported. Scheme Triazine-mediated triazole formation towards anastrozole. It has been proposed that this novel transformation occurs by a two step process: Initially, a molecule of triazine undergoes condensation and ring cleavage with the hydrazine to generate formamidrazone which then immediately reacts with a second molecule of triazine to yield the 1,2,4-triazole .
Hence, in this case the triazine can be considered as a formamide donor. Rizatriptan 76 has also been prepared by both the above mentioned procedures, i. Scheme Alternative routes to 1,2,4-triazoles. Sitagliptin , Januvia is a recently developed oral anti-diabetic drug which belongs to the dipeptyl peptidase DPP-IV inhibitor class. Consequently, insulin secretion increases leading to decreased blood glucose levels in diabetes type II patients.
In SAR studies this fused heterocycle was found to be more metabolically stable compared to earlier leads that contained a simple piperazine ring.
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Scheme Initial synthetic route to sitagliptin. In the discovery chemistry route  the heterocycle core was prepared from a S N Ar reaction between chloropyrazine and excess hydrazine. Subsequent treatment of the substituted intermediate with trifluoroacetic anhydride furnished the corresponding bis-hydrazide which underwent cyclisation at elevated temperatures in the presence of polyphosphoric acid. Finally, the partial hydrogenation of triazolopyrazine derivative with palladium on carbon gave the core triazolopiperazine An inherent problem with this synthesis was the necessity for excess hydrazine in the first step of the sequence in addition to a requirement for an expensive and only moderately efficient palladium reduction in the penultimate step.
Furthermore, the chloropyrazine starting material also proved to be unstable under a series of reaction conditions and gave rise to numerous by-products. An improved route was developed for the compounds large scale manufacture. The resulting hydrazide was then subjected to cyclodehydration using phosphoryl chloride to give a chloromethyl oxadiazole derivative In a cleverly staged transformation, this compound was treated with diaminoethane to yield the piperazine ring , which, on heating under reflux in methanol, undergoes a further condensation with the attached hydrazide to furnish the desired triazolopiperazine ring directly.
Scheme The process route to sitagliptin key intermediate HIV uses a member of the G-protein coupled receptor family called CCR-5 as an anchor to attach itself to white blood cells such as T-cells and macrophages followed by viral fusion and entry into white blood cells.
The triazole ring incorporation is achieved at an early stage by N -acylation of the tropinone fragment with 2-methylpropanoyl chloride The resulting amide is then converted to the corresponding imidoyl chloride using phosphorous pentachloride in dichloromethane which proved to be superior to phosphoryl chloride followed by condensation with acetic hydrazide It was found that the dryness of the acetic hydrazide was crucial in order to minimise the hydrolysis of the starting amide Scheme Synthesis of maraviroc.
Benzodiazepines are a well known class of compounds with a wide range of CNS-related activities. Moreover, the attachment of a third ring has been found to impact greatly on the pharmacological profile of these drugs. A representative of this compound class is alprazolam , Xanax which contains a 1,2,4-triazole fused to the benzodiazepine core.
The latter undergoes an interesting ring closure reaction in the presence of hexamine and ammonium chloride and the resulting seven membered lactam can then be converted into its thioamide analogue with P 2 S 5 in pyridine. Finally, the reaction of with acetyl hydrazide catalysed by acetic acid furnishes the triazole ring fused to the benzodiazepine core. Scheme Synthesis of alprazolam. Another approach  makes use of 1,4-benzodiazepine- N -nitrosamidine as the starting material which when treated with acetyl hydrazide undergoes the final ring closure.
Scheme The use of N -nitrosoamidine derivatives in the preparation of fused benzodiazepines. Figure 9: Structures of itraconazole, ravuconazole and voriconazole. All members of this class share a common biological activity being inhibitors of fungal cytochrome P oxidase-mediated synthesis of ergosterol. In one synthesis of itraconazole  1,2,4-triazole was introduced via direct nucleophilic substitution.
However, due to the previously discussed regioselectivity issues, extensive chromatographic purification was required following this step. In the latter stages of the synthesis, the elaborated aniline derivative was trapped with phenyl chloroformate to form the corresponding carbamate which was then converted into triazolone by a double condensation reaction with hydrazine and formamidine.
Scheme Synthesis of itraconazole. In the final step the nitrile group is quantitatively hydrolysed under basic conditions to the primary amide. Scheme Synthesis of rufinamide. Apart from this patented route, an improved approach has recently been described . In this work it was shown that the highly toxic and flammable 2-chloroacrylonitrile can be readily substituted with the less toxic and less expensive methyl 3-methoxyacrylate. After thermal cycloaddition, the methyl ester is converted to the corresponding amide by the addition of methanolic ammonia. Overall, this process can be performed as a single pot procedure on a multi-gram scale to afford rufinamide in a similarly high yield and generating less waste.
The tetrazole motif as a bioisostere for a carboxyl group is a well documented structural replacement represented by five angiotensin II antagonists in the top selling drugs. In order to generate the tetrazole ring, a nitrile is reacted with an azide, most commonly tributyltin azide. Scheme Representative tetrazole formation in valsartan.
Figure Structure of tetrazole containing olmesartan, candesartan and irbesartan. The tetrazole ring has also been introduced at the beginning of the synthesis, however, the heterocyclic ring, which has to be carried through all subsequent steps, often requires protection. Scheme Early stage introduction of the tetrazole in losartan. The tetrazole ring also appears in cilostazol , Pletal which is a selective PDE3 phosphodiesterase inhibitor used as a platelet aggregation inhibitor. Scheme Synthesis of cilostazol. The main feature of cefdinir is that it shows excellent activity against Staphylococcus species .
The thiazole ring in cefdinir shows that the heterocyclic structure in a drug not only affects its pharmacodynamic properties but can also influence its kinetics. It is believed that in the digestive tract iron II ions form chelate complexes with the thiazole ring and the oxime nitrogen atom and hence reduce the bioavailability of cefdinir . Figure Structure of cefdinir. Simultaneous trityl protection of the oxime and primary amine furnishes the desired coupling partner in good overall yield. Hydroxide promoted ester hydrolysis was followed by treatment with phosphoryl chloride and the resulting acyl chloride coupled with the biologically derived lactam All three trityl protecting groups are simultaneously cleaved with TFA to furnish cefdinir Scheme Semi-synthesis of cefdinir.
Interestingly, ritonavir itself is a result of further improvements on earlier candidates for the treatment of AIDS. A lead compound , A was also described by Abbott bearing pyridine rings on both ends of the peptidomimetic structure, which resulted in good bioavailability as required for orally administered drugs, but this compound had an insufficient plasma half-life. This was ascribed to the more electron-rich nature of the pyridine rings when compared to many other nitrogen containing heterocycles leading to a higher metabolic susceptibility.
Consequently, the pyridine rings were replaced with less electron-rich thiazoles which resulted in both good bioavailability and a long plasma half-life. In addition, H-bonding of the 5-substituted thiazole to the backbone of Asp of the HIV-1 protease is reported to be crucial with other substitution patterns showing reduced potency. Scheme Thiazole syntheses towards ritonavir. Scheme Synthesis towards pramipexole. This in turn can be treated with cyanamide to furnish the racemic thiazole . Scheme Alternative route to pramipexole. Famotidine , Pepcidine is an H 2 -receptor antagonist similar to cimetidine which inhibits many isoenzymes of the hepatic CYP system and has the additional side effect of increasing the amount of gastric bacteria such as nitrate reducing bacteria.
The structure of this ulcer therapeutic is very interesting and consists of a thiazole substituted guanidine and a sulfamoyl amidine. Although famotidine is orally administered, its solubility and hence bioavailability under acidic conditions, as found in the stomach, is relatively low. It therefore seems feasible that certain common bioavailable cations might be involved in the absorption and activation of this thiazole containing compound. The synthesis of the thiazole ring [,] can be accomplished again by condensation of thiourea with dichloroacetone Alkylation of the isothiourea sulfur with 3-chloropropionitrile and hydrolysis results in the formation of the substitution product Functionalisation of the resulting 2-amino group on the thiazole ring using benzoyl isothiocyanate generates the guanidine precursor A standard sequence of methylation and exchange with ammonia simultaneously cleaves the benzoyl group and unmasks the guanidine unit Scheme Synthesis of famotidine.
A final example of a thiazole containing drug is given in the novel xanthine oxidase inhibitor febuxostat , Uloric which was approved by the FDA in This inhibitor works by blocking xanthine oxidase in a non-competitive fashion. Consequently, the amount of the oxidation product uric acid is reduced. Thus it is an efficient treatment for hyperuricemia in gout. In order to prepare febuxostat first a synthesis of the non-commercial 4-isobutoxy-1,3-dicyanobenzene building block , has to be conducted. It is suggested that a Meisenheimer-complex intermediate is initially formed, which after rearomatisation, undergoes nucleophilic aromatic substitution of the nitro group by the DMSO solvent .
Upon hydrolysis and O -alkylation the desired 4-isobutoxy-1,3-dicyanobenzene is obtained in good overall yield. Subsequently, the less hindered nitrile is converted to the corresponding thioamide in an intriguing reaction using thioacetamide Scheme Efficient synthesis of the hyperuricemic febuxostat. The exact pharmacological effect of ziprasidone is not simple to understand as it affects many subtypes of dopamine, adrenergic and serotonin receptors. However, like many antipsychotic drugs its main therapeutic activity is probably due to its antagonistic action on dopamine receptors.
The molecule comprises of a 1,2-benzisothiazole core, which is readily prepared from commercially available benzo[ d ]isothiazol-3 2 H -one , a saccharin derivative . The corresponding chloroimidate formed by treatment of compound with phosphoryl chloride is reacted with excess piperazine to afford intermediate Route A . Therefore an improved process was developed involving the oxidative coupling of piperazine with bis 2-cyanophenyl disulfide at elevated temperatures . Due to the use of DMSO as a co-solvent and oxidant, each equivalent of the disulfide component was then converted into two equivalents of the product making the process more economically efficient.
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Scheme Synthesis of ziprasidone. Mometasone , Nasonex is one of the few examples amongst the top selling pharmaceutical drugs that contains a furan ring. Simple furan structures are not normally viable because of their propensity for rapid metabolism by various oxidation mechanisms. Mometasone is a moderately potent glucocorticoid used for the treatment of inflammatory skin disorders, asthma and allergic rhinitis. Because it is delivered topically or is inhaled, it is not subject to rapid metabolism.
Figure Structure of mometasone. Corncobs contain hemicelluloses which degrade to xylose under acidic conditions. Scheme Industrial access to 2-furoic acid present in mometasone. In the synthesis of this H 2 -receptor antagonist, furfuryl alcohol is subjected to a Mannich reaction with paraformaldehyde and dimethylamine hydrochloride.
The resultant 5- dimethylamino methyl furanyl methanol is then treated with cysteamine hydrochloride which leads to replacement of the hydroxyl functionality. Scheme Synthesis of ranitidine from furfuryl alcohol. In addition, the antibiotic nitrofurantoin , Macrobid used in the treatment of urinary infections is based on a nitrofurfural building block which can be obtained by nitration of furfural .
Scheme Synthesis of nitrofurantoin. Amiodarone , Cordarone is an antiarrhythmic drug containing a benzofuran ring system. It is one of the most effective antiarrhytmic drugs. Although it is considered a class III antiarrhytmic with its mode of action being principally the blocking of potassium channels, it is anticipated that it is also capable of targeting additional sodium and calcium channels. This might explain its general effectiveness, but could also account for its potentially dangerous side effects. Scheme Synthesis of benzofuran. A Friedel—Crafts acylation next introduces the aryl ring at the 3-position.
Demethylation, iodination and a final alkylation with a diethylaminoethane fragment yields amiodarone . Scheme Synthesis of amiodarone. Considering the fact that thiophene is a classical bioisostere for a benzene ring it is not surprising that it is encountered in many therapeutically active agents. Amongst the drugs containing a thiophene ring are raloxifene , Evista and olanzapine Zyprexa. The former, which is a benzo[ b ]thiophene, is widely used as an oral selective estrogen receptor modulator displaying estrogenic actions on bone prevention of osteoporosis and anti-estrogenic actions on breast and uterus, especially in the postmenopausal women .
Further transformations on this scaffold include the introduction of the carbonyl at the 3-position via a Friedel—Crafts acylation and deprotection, yields raloxifene. Scheme Synthesis of raloxifene. The vinylic sulfoxide undergoes a formal electrophilic cyclisation under the acidic conditions followed by aromatisation to furnish the desired intermediate in high yield.
Scheme Alternative access to the benzo[ b ]thiophene core of raloxifene. Another atypical antipsychotic drug which has been long established as a top-selling pharmaceutical is olanzapine which was first introduced to the market by Eli Lilly in The thiophene unit is synthesised by a multi-component reaction between malononitrile, elemental sulfur and propionaldehyde in the presence of triethylamine.
This species is then employed in a nucleophilic aromatic substitution with 2-fluoronitrobenzene to give the coupled product Reduction of the nitro functionality produces the corresponding aniline that readily undergoes ring closure to furnish ultimately the thienobenzodiazepine Scheme Gewald reaction in the synthesis of olanzapine. The previously used nucleophilic substitution was repeated to furnish the methyl ester analogue Scheme Alternative synthesis of olanzapine.
However, the syntheses of all three compounds use simple thiophene starting materials, viz. Figure Access to simple thiophene-containing drugs. Subsequent hydrolysis of the secondary nitrile under phase transfer conditions delivers the free acid which is converted to the methyl ester In order to obtain the desired S -enantiomer, a classical resolution with ca. The remaining material can be easily epimerised under mildly basic conditions.
Scheme Synthesis of clopidogrel. Although the tetrahydrothieno[3,2- c ]pyridine structure is now readily available on a large scale from various commercial sources, it was originally synthesised in a variety of ways. The most straightforward route was from thiophenecarbaldehyde which was subjected to a Henry reaction with nitromethane. Reduction of the nitro olefin function to the corresponding alkylamine followed by reaction with formaldehyde gave the corresponding imine .
Scheme Pictet—Spengler reaction in the preparation of tetrahydrothieno[3,2- c ]pyridine This key compound can also be accessed by assembling the thiophene ring. In this scenario N -protected 4-piperidone is subjected to Vilsmeier conditions to produce the reactive chloroaldehyde species which, upon treatment with ethyl mercaptoacetate , cyclises to the heterocyclic structure although in only low isolated yield.
Scheme Alternative synthesis of key intermediate Additionally, this data nicely exemplifies the stronger binding of timolol, as its morpholine group is involved in an extra hydrogen-bonding network with nearby amino acids Asn, Tyr, Ser and the thiadiazole motif itself protrudes deeper into the actual binding pocket when compared with the carbazole system of carazolol which results in stronger interactions.
The active pharmaceutical ingredient API timolol is prepared via a biocatalytic asymmetric reaction which permits selective access to both enantiomers . Starting from 3,4-dichloro-1,2,5-thiadiazole , which can be prepared from cyanogen and sulfur dichloride  , the two chlorides are differentiated by sequential substitution reactions using morpholine and sodium hydroxide. The levorotatory enantiomer thus obtained can be subjected to Mitsunobu conditions with benzoic acid as the nucleophile and leads to clean inversion of the stereocentre which thus gives access to the other enantiomer of timolol.
Scheme Synthesis of timolol. A related heterocyclic structure can be found in the skeletal muscle relaxant tizanidine , Zanaflex. This substituted 2,1,3-benzothiadiazole can be prepared by the reaction of an aromatic diamine on heating with thionyl chloride in the presence of DMF. Selective nitration followed by an iron-mediated reduction affords the corresponding aniline which partakes in a nucleophilic substitution of 2-chloro-3,4-dihydroimidazole generated in situ from the reaction of the urea and phosphoryl chloride.
Scheme Synthesis of tizanidine The isoxazole ring is a common heterocyclic motif represented by several of the top-selling small molecule pharmaceuticals. This ring structure is often encountered as a surrogate of other nitrogen containing heterocycles such as pyrazoles, pyridines or pyrimidines . Two specific drugs containing this structure are leflunomide , Arava and sulfamethoxazole , Bactrim.
DMARDs are not necessarily structurally or mechanistically related. The effect of leflunomide is possibly due to its regulation of the immune system via affecting lymphocytes. Its synthesis  is relatively straightforward starting with a Knoevenagel condensation of ethyl acetoacetate 39 and triethyl orthoformate in the presence of acetic anhydride.
The resulting ethyl ethoxymethylene acetoacetate is next condensed with hydroxylamine hydrate in methanol to yield ethyl 5-methylisoxazolecarboxylate Scheme Synthesis of leflunomide. This basic unit is then nitrated with a mixture of ammonium nitrate in trifluoroacetic anhydride , which is presumed to form the active trifluoroacetyl nitrate, and converted to the 3-aminomethylisoxazole in a aluminium-amalgam mediated reduction [,].
Scheme Synthesis of sulfamethoxazole. The most prescribed therapeutic for schizophrenia is the benzisoxazole containing antipsychotic risperidone , Risperdal. For this molecule the benzisoxazole ring is formed via an intramolecular nucleophilic aromatic substitution between an in situ generated oxime and the adjacent aromatic ring . The precursor carbonyl derivative arises from a Friedel—Crafts acylation of the difluoroaromatic the acetate N -protecting group is presumably lost in the work up. Scheme Synthesis of risperidone. Having collected data with respect to many different reported syntheses of drugs containing heteroaromatic five-membered rings, a number of observations can be drawn.
Other well represented transformations include reductions, amide and ester formations, rearrangements and saponifications, which can be performed in an atom-economic manner based on numerous well established protocols. On the other hand, other robust transformations such as oxidations, nucleophilic aromatic substitutions, olefinations, cycloadditions and metal-mediated transformations appear to be rarely used.
The reasons for this might be the need for stoichiometric reagents leading to large amounts of waste as well as potential heavy metal contamination. In addition, these reactions are usually accompanied by the release of heat due to exothermic reaction profiles which might result in difficult to control and therefore undesired chemical processes. Figure Relative abundance of selected transformations.
An additional comment should be made about the time frame of new reaction uptake within the process environment. For certain reaction types such as metathesis and C—H activation, which obviously offer significant synthetic potential, it could be argued that the length of time required for these reactions to evolve from research tools to production processes are outwith the pipeline development times of the drugs under discussion.
A significant body of the literature representing the synthesis of these drugs date back many years to origins in the late seventies and early eighties. However, the more recent trend seems to indicate a move towards more diverse scaffolds. This might be ascribed to the massive efforts of the pharmaceutical industry to find new drug classes, but could also be an indication of the patenting approaches used to protect more comprehensively these new developments. Furthermore, this move towards novel heterocyclic structures also allows for more flexible substitution patterns permitting extensive SAR studies through efficient high throughput screenings commonly used today.
Figure The abundance of heterocycles within top drugs 5-membered rings. One constant in all the drug syntheses is the shortness of the reported routes, which typically do not exceed 6—8 steps. It is predicted  that the number of future drugs bearing chirality will increase due to more reliable and affordable catalytic asymmetric transformations . Based on the material presented in this review it can be concluded that most of the reported routes towards well established drugs are based on conventional transformations to furnish the desired compound quickly. In order to achieve the necessary productivity gains future chemistry programmes will have to employ a wider range of synthetic transformations targeted at delivering molecules covering an expanded area of chemical space.
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An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals
Ian R. Steven V. Nikzad Nikbin. Review PDF Album. Graphical Abstract. Pyrroles Pyrrole, a five-membered nitrogen containing heterocycle is present in some of the most common biologically important molecules, i. Jump to Figure 1. Jump to Figure 2. Jump to Scheme 1. Jump to Scheme 2. Jump to Scheme 3. Jump to Scheme 4. Jump to Scheme 5. Jump to Scheme 6.
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Jump to Figure 3. Jump to Scheme 7. Jump to Scheme 8. Jump to Scheme 9. Jump to Scheme Jump to Figure 4. Jump to Figure 5. Jump to Figure 6. Jump to Figure 7. Jump to Figure 8. Jump to Figure 9. Jump to Figure Trans [2- 3- or 4-carboxamido-substituted pyrrolyl alkyl]hydroxypyranone Inhibitors of Cholesterol Synthesis.
Patent 4,,, July 21, Improved Process for Trans[2- substituted-pyrroleyl alkyl]pyranone Inhibitors of Cholesterol Synthesis.
Process for the Synthesis of 5 R -1,1-Dimethylethylcyanohydroxyoxohexanoate. Patent 5,,, Oct 13, Heterocycles , 48, — Indole Derivative. Patent 5,,, Aug 6, Heterocycles , 53, — Synthesis , 12, — Preparation of Indole Derivatives. Patent 5,,, April 7, Process for the Preparation of N-Methyl 1-methylpiperidinyl indoleethanesulphonamide. Method for the Preparation of Zolmitriptan. Triazole Containing Indole Derivatives. Patent 5,,, March 29, An Improved Process for the Preparation of Rizatriptan. Improved Process for the Preparation of Rizatriptan Benzoate.
Indole Derivatives. Patent 5,,, Aug 13, Process for the Preparation of 3-Acylindoles. The Iron atom is a vital center for oxidation of substrates drugs or other xenobiotics. Rotate and re-size as necessary to shown that the heme is highly planar. Do you recognize the 4 pyrrole rings within the heme? Examine the iron atom in the heme. It is capable of forming 6 bonds. Four of those are with the 4 pyrrole rings that make up the porphyrin ring system. The fifth and sixth bonds are made to atoms above and below the plane of heme ring.
The fifth is made to a cysteine residue present on the protein. The final bond is made to an oxygen molecule not shown. This molecular oxygen is activated to aid in oxidation of substrates and would appear directly between the substrate and the iron atom. The cysteine residue that coordinates with the iron atom is vital; it helps to polarize the heme allowing heme to bind with oxygen.
This residue is highly conserved throughout all of the known CYPs. The bond between the sulfur atom of the cysteine residue and the heme ring is shown in yellow. Note that the sixth site for a bond with iron remains unfilled and available to bind to oxygen. Although the presence of the cysteine residue is invariable in all CYPs, the other residues that surround it may vary.
This can affect the shape of the active site and the drugs that can bind there. Now let's take a look at being oxidized while noting its orientation relative to the heme group. Re-size and rotate the molecules until you can see how the two molecules are oriented in relationship to each other. The flavone is metabolized oxidized by introduction of a hydroxy group onto the phenyl ring attached to the tricyclic ring system. Note, in particular, the distance and orientation of the heme Iron and the phenyl substituent.
When some drugs are administered to humans, the metabolites observed may be the result of oxidation at more than one position in the molecule. What factors do you think might contribute to this? Several factors may come into play. First, more than one CYP isoform may be contributing to the drug's metabolism, with each isoform preferring different sites of attack.
When examining certain specific CYP isoforms like CYP1A2 there is also the possibility that attack may occur at more than one position, giving more than one metabolite. What factors do you think might lead to this? In this example, purely based on the distance between the phenyl ring of the flavone and the heme iron, oxidation might be expected to take place at the 4 para position. However, other factors may also help determine the regioselectivity of the metabolism selectivity for oxidation at the different possible positions.
One of these factors is the relative reactivity of the various positions on the substrate. Different CYPs have preferences for oxidizing different substrates. Some of them have a much narrower range of molecular structures that they can oxidize. CYP1A2 preferentially oxidizes molecules that are relatively large and planar, as in this structure . The complementary size and shape of the drug and binding site makes them a good match for each other.
The substrate flavone shown here is different from many other substrates of this CYP. Besides being a substrate of CYP1A2, it is also a competitive inhibitor . It can inhibit the metabolism of other CYP1A2 substrates because it binds very tightly to it. Thus, while the CYP is inhibited, it is unavailable to metabolize other substrates e. Therefore, if a second drug that is a CYP1A2 substrate is co-administered with this compound, it might not be broken down as expected, and could build up to toxic levels. The reason that this flavone is bound so tightly to the enzyme is that its shape and electronic charges are complementary to the binding pocket.
This is examined in the next section. First examine the shape of the around the flavone. The range of bluish-green to reddish-orange colored areas on the surface differentiate how close red , or how far blue , in proximity the flavone is to the binding pocket. These contacts can be caused by ionic, hydrophobic, or hydrogen bonding.
Given the structure of the flavone, what forces do you suspect may be responsible for binding the enzyme so tightly? In the next scene, the Van der Waals surface of the is displayed. The portions of the cavity involved in binding are shown as orange patches. These are a result of specific amino acid residues that form the surface of the binding pocket. Clicking on this will show the surface of the flavone and a few of the most important amino acid residues responsible for binding. As you rotate the molecule, look at how each of the amino acid residues at the active site is interacting with parts of the flavone.
Can you predict what kinds of interactions H-bonds, lipophilic, or ionic might be made? Examine the hydrophobic portions of the inhibitor. What kind of residues would interact with these? Is the label consistent with your expectations for these kinds of interactions? Since the CYPs largely metabolize hydrophobic substrates, hydrophobic interactions are very important for binding many substrates.
That is clearly the case here. The next ligand discussed fits exceptionally well into the binding pocket due to the principle of induced fit. Induced fit occurs when a drug binds to a protein and causes a conformational change that leads to tighter binding. Thus the "fit" of the drug to the protein is "induced" in many cases.
A molecule that is able to induce a fit to a protein might be expected to exhibit competitive inhibition. This helps explain the fact that it is the enzyme most commonly associated with undesired drug-drug interactions. A number of these drugs are known to cause potentially dangerous or even fatal interactions. The reason that CYP3A4 is involved in the metabolism of so many drugs appears to be related to the size and flexibility of its binding pocket, which can accommodate a number of fairly large drugs. A few drugs considered to be "large" include macrolide antibiotic erythromycin, the anticancer drug taxol, the immunosuppressant cyclosporine, and several statins.
Examining the way drugs bind to CYP3A4 gives some insight into its selectivity and the way it may be influence the pharmacokinetics of the drug. In the crystal structure of CYP3A4 bound to erythromycin, the volume of the active site is notably different than the ligand-free active site. With erythromycin being a fairly large drug MW CYP1A2 cannot accommodate it and therefore cannot metabolize it.
Due to its flexible binding pocket, CYP3A4 can also accommodate a diversity of other, smaller substrates. The following scene shows the ligand-free form of. The next scene shows the of CYP3A4 without a substrate. Examine the size and shape of the cavity by rotating and resizing the molecule.
Observe that the cavity extends toward the heme ring and is located more so on the periphery. In order for a drug to be oxidized, it must come quite close to the oxygen atom held by the heme. It is important to realize that a change must occur in order for the binding pocket to be oriented in a way that is conducive to allowing metabolism to occur.
Now, take a look at this scene showing PDB entry 2j0d. The cavity is now in closer proximity to the heme ring and the shape of the cavity has changed as well. In this case, CYP3A4 has undergone a conformational change as a result of binding to erythromycin. In comparing the bound and unbound structures, it looks as though the enzyme has adopted a conformation that allows the drug to occupy the pocket more specifically tailored to its size and shape for a tighter fit. You will also notice that there is an opening in the cavity where erythromycin entered.