Biotransformation Reactions of Five-Membered Aromatic Heterocyclic Rings

Dalvie, Deepak; Kalgutkar, Amit S.; Khojasteh-Bakht, Siamak C.; Obach, R. Scott; O’Donnell, John P.

doi:10.1021/tx015574b

Cited by 475 publications

(372 citation statements)

References 165 publications

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“…In vitro potency, MLM, and glucuronidation data for select JNK inhibitors. 64 elimination through glucuronidation, 13 but analogues 101 and 102 were both relatively stable in a glucuronidation assay.…”

Section: ■ Heteroaromatic Compoundsmentioning

confidence: 98%

“…Also, if the five-membered ring on compound 104 is the site of metabolism, the 1,2,4-oxadiazole ring may undergo metabolic N−O ring-opening, which is precedented in the literature. 13,66 Without an N−O bond, the 1,3,4-oxadiazole ring on 105 would not undergo this route of metabolism. 67 In their work on dipeptidyl peptidase IV (DPP-4) inhibitors for the treatment of type 2 diabetes, Nordhoff et al determined the metabolic stability of a number of three-heteroatom fivemembered heterocycles (Figure 31).…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

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Mitigating Heterocycle Metabolism in Drug Discovery

2012

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In the past few decades, drug metabolism research has played an ever increasing role in the design of drugs. 1−3 In vitro metabolism assays 4 have become an integral part of the routine profiling of compounds made in drug discovery. 5 The data from these assays have allowed medicinal chemists to focus their efforts on compounds with improved metabolic stability. 6 Detailed metabolite identification studies are also done more routinely, which provide information on how to strategically replace or block metabolically labile sites. 7 Additionally, in vivo PK studies are regularly conducted in drug discovery, which helps to build in vitro−in vivo PK relationships. 4 The positive influence that these advances in PKDM sciences have had on drug discovery is reflected in the fact that fewer drug candidates fail in the clinic for PKDM related issues. 8 This suggests that medicinal chemists are successfully integrating the data generated by their PKDM colleagues into the design of compounds with fewer metabolic liabilities.Extensive data from metabolism studies have allowed medicinal chemists to develop general principles for reducing compound metabolism. These methods include, but are not limited to, reducing lipophilicity, altering sterics and electronics, introducing a conformational constraint, and altering the stereochemistry of their compounds. While no single method is able to solve every metabolic problem, these principles do give medicinal chemists guidance on how to improve the metabolic liabilities of their compounds. If the specific site of metabolism is known, medicinal chemists block the site, typically with a fluorine, or replace the metabolically labile group with a bioisostere. 9 While several authors have reviewed these techniques for reducing metabolism, 5,10,11 there is no review that summarizes different approaches to improving the metabolic stability of heterocycles. In this review, we summarize examples where changes were made at or near the heterocycle to improve metabolic stability. By summarizing these examples, we hope to provide a useful guide to medicinal chemists as they attempt to improve the metabolic profile of their own heterocyclic compounds.The majority of the examples that are included in this review came from searching the online open access database CHEMBL. 12 In addition to having pharmacology data on compounds from the medicinal chemistry literature, CHEMBL has over 120 000 points of data on the ADMET properties of compounds. With the help of the visualization software Spotfire, we were able to cull examples from the CHEMBL ADMET data that focused on heterocycles. We also identified examples from papers that cite leading reviews in the drug metabolism field 13−18 and were present in other recent reviews on drug metabolism. 19−22 The main criteria that we placed on the examples selected for this review was that the change made to improve metabolism had to occur at or near the heterocycle and nowhere else on the molecule. This allowed us to eliminate examples where a change made t...

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Section: ■ Heteroaromatic Compoundsmentioning

confidence: 98%

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Mitigating Heterocycle Metabolism in Drug Discovery

2012

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“…C5-hydroxylation, however, is quantitatively unimportant because thiazoles do not readily undergo electrophilic substitution reactions (Rance, 1989). EFSA Journal 2011; 9(10):1989 Alkyl-and acyl-substituted thiazole derivatives can be metabolised via side-chain oxidation and ring S-and N-oxidation (Dalvie et al, 2002). The major metabolites are readily excreted in the urine either free or as glutathione conjugates.…”

Section: Additional Information For Candidate Substances In Subgroup mentioning

confidence: 99%

Scientific Opinion on Flavouring Group Evaluation 21, Revision 2 (FGE.21Rev2): Thiazoles, thiophene, thiazoline and thienyl derivatives from chemical group 29. Miscellaneous substances from chemical group 30

Flavourings¹

2011

EFSA Journal

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The Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids of the European Food Safety Authority was requested to evaluate 56 flavouring substances in the Flavouring Group Evaluation 21, Revision 2, using the Procedure in Commission Regulation (EC) No 1565/2000. Seven of the substances 15.086, 15.090, 15.099, 15.114, 15.119 and 15.133] were considered to have genotoxic potential. The remaining 49 substances were evaluated through a stepwise approach (the Procedure) that integrates information on structure-activity relationships, intake from current uses, toxicological threshold of concern, and available data on metabolism and toxicity. The Panel concluded that 26 substances 15.039, 15.044, 15.050, 15.051, 15.052, 15.058, 15.061, 15.062, 15.063, 15.067, 15.068, 15.069, 15.071, 15.078, 15.080, 15.082, 15.084, 15.085, 15.087, 15.089, 15.098, 15.108, 15.115, 15.116 and 15.118] do not give rise to safety concerns at their levels of dietary intake, estimated on the basis of the MSDI approach. For the remaining 23 candidate substances 15.040, 15.042, 15.043, 15.045, 15.054, 15.055, 15.064, 15.070, 15.072, 15.074, 15.076, 15.077, 15.088, 15.091, 15.092, 15.093, 15.094, 15.096, 15.097, 15.106, 15.107 and 15.129], of the 49 substances evaluated through the Procedure, no appropriate NOAEL was available and additional data are required. Besides the safety assessment of these flavouring substances, the Flavouring Group Evaluation 21, Revision 2 2 EFSA Journal 2011; 9(10):1989 specifications for the materials of commerce have also been considered. For two substances are an identity test lacking and for one has the stereoisomeric composition to be specified. In the present FGE.21Rev2, the 56 candidate substances include five-and six-membered sulphurcontaining aromatic and non-aromatic heterocycles, which have been arranged into 11 subgroups in order to facilitate comparisons of the data sets between the groups. This division was done on the basis of degree of aromaticity and according to the presence of other heteroatoms (i.e. nitrogen).Five of the 56 candidate substances possess one chiral centre Forty-six of the 56 candidate substances are classified into structural class II and 10 candidate substances are classified into structural class III, according to the decision tree approach presented by Cramer et al., 1978. Forty-two of 56 the candidate substances have been reported to occur in a wide range of food items.In its evaluation, the Panel as a default used the "Maximised Survey-derived Daily Intake" (MSDI) approach to estimate the per capita intakes of the flavouring substances in Europe. However, when the Panel examined the information provided by the European Flavour Industry on the use levels in various foods, it appeared obvious that the MSDI approach in a number of cases would grossly underestimate the intake by regular consumers of products flavoured at the use level reported by the Industry, especially in those cases where the annual production values were reported to be small. ...

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“…2 1,2,3-Triazole can serve as a suitable moieties in these drugs since it is stable to metabolic degradation and susceptible to hydrogen bonding beneficial for the affinity with molecular targets and solubility. 3,4 Compounds containing a 1,2,3-triazole moiety show various biological activities such as anti-HIV, 5 anti-microbial, 6 anti-allergic, 7 and selective b3 adrenergic receptor agonist. 8 Ribavirin (Fig.…”

Section: Introductionmentioning

confidence: 99%

An Efficient Synthesis of Mono and Bis‐1,2,3‐triazole AZT Derivatives via Copper(I)‐catalyzed Cycloaddition

Yuan

Chen

et al. 2011

J Chinese Chemical Soc

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An efficient synthesis of novel mono and bis-1,2,3-triazoles 3¢-azido-2¢-deoxythymidine (AZT) derivatives via copper(I)-catalyzed 1,3-dipolar cycloaddition reaction is described. Starting from AZT and terminal alkyne derivatives, mono and bis-1,2,3-triazole AZT derivatives are regioselectively obtained in good yields under mild conditions using CuSO 4 ·5H 2 O and sodium ascorbate as a catalyst system, and t-BuOH/H 2 O (1:1, v/v) as a co-solvent. The structures of these compounds were elucidated by IR, HR MS and NMR.

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Biotransformation Reactions of Five-Membered Aromatic Heterocyclic Rings

Cited by 475 publications

References 165 publications

Mitigating Heterocycle Metabolism in Drug Discovery

Mitigating Heterocycle Metabolism in Drug Discovery

Scientific Opinion on Flavouring Group Evaluation 21, Revision 2 (FGE.21Rev2): Thiazoles, thiophene, thiazoline and thienyl derivatives from chemical group 29. Miscellaneous substances from chemical group 30

An Efficient Synthesis of Mono and Bis‐1,2,3‐triazole AZT Derivatives via Copper(I)‐catalyzed Cycloaddition

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