A Rational Chemical Intervention Strategy To Circumvent Bioactivation Liabilities Associated with a Nonpeptidyl Thrombopoietin Receptor Agonist Containing a 2-Amino-4-arylthiazole Motif

Kalgutkar, Amit S.; Driscoll, James P.; Zhao, Sabrina X.; Walker, Gregory S.; Shepard, Richard M.; Soglia, John R.; Atherton, James; Yu, Linning; Mutlib, Abdul; Munchhof, Michael J.; Reiter, Lawrence A.; Jones, Christopher S.; Doty, Johnathan L.; Trevena, Kristen A.; Shaffer, Christopher L.; Ripp, Sharon L.

doi:10.1021/tx700270r

Cited by 52 publications

(34 citation statements)

References 46 publications

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“…The corresponding S-oxide has been trapped with GSH to give the GSH conjugate. A similar reaction has also been observed with compounds containing a thiazole ring as exemplified in the metabolism of the nonpeptidyl thrombopoietin receptor agonist [140].…”

Section: Epoxidation Of Arenes and Olefinssupporting

confidence: 58%

Bioactivation I: Bioactivation by Cytochrome P450s

Dalvie

2012

Encyclopedia of Drug Metabolism and Interactions

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Metabolism reactions generally result in detoxification of xenobiotics and are accompanied by the formation of chemically stable metabolites, which are devoid of pharmacological or toxicological activities. However, in some cases, these reactions can convert drugs to products that are either chemically reactive or pharmacologically active, a process that is commonly referred to as metabolic activation or bioactivation . Most, if not all, functionalization and conjugation reactions can result in bioactivation. Even though all enzymes have the propensity to catalyze the metabolic activation of compounds, cytochrome P450 (P450) enzymes, which generally dominate metabolism, play a major role in the metabolic activation of drugs. The primary objective of this chapter is to provide an overview of bioactivation by P450 to pharmacologically active and chemically reactive metabolites. The common reactions that result in bioactivation of xenobiotics and consequences of bioactivation have been discussed here.

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Section: Epoxidation Of Arenes and Olefinssupporting

confidence: 58%

Bioactivation I: Bioactivation by Cytochrome P450s

Dalvie

2012

Encyclopedia of Drug Metabolism and Interactions

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“…54 However, incorporation of a fluorine (82) or nitrogen (83) at the C-5 position of the thiazole prevented the bioactivation pathway from occurring. The rat in vivo PK for these two new analogues was also better than the parent compound.…”

Section: ■ Heteroaromatic Compoundsmentioning

confidence: 99%

“…In vivo PK was measured in male SD rats (1 mg/kg iv, 5 mg/kg po). 54 one of the initial leads in their program, but in monkey PK studies, the α,β-unsaturated ketone present in 94 underwent metabolism to give the corresponding saturated alcohol. Part of the strategy to circumvent this problem was to reduce the double bond and replace the ketone with five-membered heteroarenes.…”

Section: ■ Heteroaromatic Compoundsmentioning

confidence: 99%

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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“…Consequently, the 2-methylimidazo[2,1-b][1,3,4]thiadiazole analog 3 was synthesized to prevent thiazole ring epoxidation and/or addition of GSH to an S-oxide metabolite. An identical medicinal chemistry strategy had been successfully used to abrogate thiazole ring bioactivation with nonpeptidyl thrombopoietin receptor agonists containing the 2-aminothiazole motif (Kalgutkar et al, 2007). As such, the absence of the GSH conjugate formation in NADPH-and GSH-supplemented HLM incubations with 3 indicates that the thiadiazole derivative is devoid of the reactive metabolite liability associated with 1 and 2 and demonstrates the success of this medicinal chemistry tactic.…”

Section: Discussionmentioning

confidence: 98%

Reactive Metabolite Trapping Studies on Imidazo- and 2-Methylimidazo[2,1-b]thiazole-Based Inverse Agonists of the Ghrelin Receptor

et al. 2013

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The current study examined the bioactivation potential of ghrelin receptor inverse agonists, 1-{2-[2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl]-2,7-diazaspiro[3.5]nonan-7-yl}-2-(imidazo[2,1-b]thiazol-6-yl)ethanone (1) and 1-{2-[2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl]-2,7-diazaspiro[3.5]nonan-7-yl}-2-(2-methylimidazo[2,1-b]thiazol-6-yl) ethanone (2), containing a fused imidazo[2,1-b]thiazole motif in the core structure. Both compounds underwent oxidative metabolism in NADPH-and glutathione-supplemented human liver microsomes to yield glutathione conjugates, which was consistent with their bioactivation to reactive species. Mass spectral fragmentation and NMR analysis indicated that the site of attachment of the glutathionyl moiety in the thiol conjugates was on the thiazole ring within the bicycle. Two glutathione conjugates were discerned with the imidazo[2,1-b]thiazole derivative 1. One adduct was derived from the Michael addition of glutathione to a putative S-oxide metabolite of 1, whereas, the second adduct was formed via the reaction of a second glutathione molecule with the initial glutathione-S-oxide adduct. In the case of the 2-methylimidazo[2,1-b]thiazole analog 2, glutathione conjugation occurred via an oxidative desulfation mechanism, possibly involving thiazole ring epoxidation as the rate-limiting step. Additional insights into the mechanism were obtained via 18 O exchange and trapping studies with potassium cyanide. The mechanistic insights into the bioactivation pathways of 1 and 2 allowed the deployment of a rational chemical intervention strategy that involved replacement of the thiazole ring with a 1,2,4-thiadiazole group to yield 2-,4]thiadiazol-6-yl)ethanone (3). These structural changes not only abrogated the bioactivation liability but also retained the attractive pharmacological attributes of the prototype agents.

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A Rational Chemical Intervention Strategy To Circumvent Bioactivation Liabilities Associated with a Nonpeptidyl Thrombopoietin Receptor Agonist Containing a 2-Amino-4-arylthiazole Motif

Cited by 52 publications

References 46 publications

Bioactivation I: Bioactivation by Cytochrome P450s

Bioactivation I: Bioactivation by Cytochrome P450s

Mitigating Heterocycle Metabolism in Drug Discovery

Reactive Metabolite Trapping Studies on Imidazo- and 2-Methylimidazo[2,1-b]thiazole-Based Inverse Agonists of the Ghrelin Receptor

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