A new structural alert for benzimidazoles: 2,6-Dimethylphenyl substituents increase mutagenic potential and time-dependent CYP3A4 inhibition risk

Kwak, Young‐Shin; Coppola, Gary M.; Forster, Cornelia; Gilmore, Thomas A.; Gong, Yongjin; Kanter, Aaron; Neubert, Alan D.; Stroup, Bryan; Szklennik, Paul V.; Glowienke, Susanne; Stadelmann, Pascal; Bell, Leslie; Bickford, Shari; Gangl, Eric; Gunduz, Mithat; Jain, Mohit; Zhan, Jenny; Serrano‐Wu, Michael H.

doi:10.1016/j.bmcl.2011.01.023

Cited by 3 publications

(4 citation statements)

References 17 publications

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“…This finding was particularly satisfying as we had previously identified that a benzimidazole substituted with 2,6-dimethylphenyl group at C-2, a partial structure present in 6 , can serve as a toxicophore for such a risk via generation of a reactive metabolite of proposed structure 10 after metabolic oxidation (Scheme ). , Although 9 contains the same structural motif, observation of a metabolite 11 during biotransformation studies on 9 implies a shift in metabolism from the benzimidazole moiety to the methoxy group, avoiding the formation of 10 .…”

Section: Resultsmentioning

confidence: 99%

“…structure 10 after metabolic oxidation (Scheme 1). 21,22 Although 9 contains the same structural motif, observation of a metabolite 11 during biotransformation studies on 9 23 implies a shift in metabolism from the benzimidazole moiety to the methoxy group, avoiding the formation of 10.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Methyl 3-(4-Formyl-3,5-dimethylphenyl)-2,2-dimethylpropanoate (21). Zn−Cu couple (1.3 g) was stirred in toluene (16 mL) and dimethylacetamide (2 mL) at room temperature under nitrogen for 15 min.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Discovery of an Orally Bioavailable Benzimidazole Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor That Suppresses Body Weight Gain in Diet-Induced Obese Dogs and Postprandial Triglycerides in Humans

Nakajima¹,

Chatelain²,

Clairmont³

et al. 2017

J. Med. Chem.

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Modification of a gut restricted class of benzimidazole DGAT1 inhibitor 1 led to 9 with good oral bioavailability. The key structural changes to 1 include bioisosteric replacement of the amide with oxadiazole and α,α-dimethylation of the carboxylic acid, improving DGAT1 potency and gut permeability. Since DGAT1 is expressed in the small intestine, both 1 and 9 can suppress postprandial triglycerides during acute oral lipid challenges in rats and dogs. Interestingly, only 9 was found to be effective in suppressing body weight gain relative to control in a diet-induced obese dog model, suggesting the importance of systemic inhibition of DGAT1 for body weight control. 9 has advanced to clinical investigation and successfully suppressed postprandial triglycerides during an acute meal challenge in humans.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

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Discovery of an Orally Bioavailable Benzimidazole Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor That Suppresses Body Weight Gain in Diet-Induced Obese Dogs and Postprandial Triglycerides in Humans

Nakajima¹,

Chatelain²,

Clairmont³

et al. 2017

J. Med. Chem.

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“…Compounds containing benzimidazole and amino-benzimidazole rings have been shown to undergo metabolic activation to form reactive metabolites . In such scaffolds, the embedded ortho arrangement of the two imidazole nitrogen atoms is likely to contribute toward the high electron density in the ring.…”

Section: Resultsmentioning

confidence: 99%

N-Aryl-2-aminobenzimidazoles: Novel, Efficacious, Antimalarial Lead Compounds

Ramachandran

P²,

Srivastava³

et al. 2014

J. Med. Chem.

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From the phenotypic screening of the AstraZeneca corporate compound collection, N-aryl-2-aminobenzimidazoles have emerged as novel hits against the asexual blood stage of Plasmodium falciparum (Pf). Medicinal chemistry optimization of the potency against Pf and ADME properties resulted in the identification of 12 as a lead molecule. Compound 12 was efficacious in the P. berghei (Pb) model of malaria. This compound displayed an excellent pharmacokinetic profile with a long half-life (19 h) in rat blood. This profile led to an extended survival of animals for over 30 days following a dose of 50 mg/kg in the Pb malaria model. Compound 12 retains its potency against a panel of Pf isolates with known mechanisms of resistance. The fast killing observed in the in vitro parasite reduction ratio (PRR) assay coupled with the extended survival highlights the promise of this novel chemical class for the treatment of malaria.

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Genotoxicity

Kirchner

Schnider²

2021

The Medicinal Chemist's Guide to Solving ADMET Challenges

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The assessment of the potential of a new drug to cause genotoxicity is a prerequisite for its progression to clinical development. This chapter gives a concise overview of the major aspects relating to genotoxicity, which are relevant in small molecule drug discovery. Testing schemes and assays recommended by regulatory guidelines are outlined. The different ways by which small molecules and their metabolites can elicit genotoxicity by DNA-reactive (direct) or non-DNA-reactive (indirect) mechanisms are discussed. Strategies to mitigate the most prevalent mechanisms of small molecule induced genotoxicity are provided and illustrated by examples.

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A new structural alert for benzimidazoles: 2,6-Dimethylphenyl substituents increase mutagenic potential and time-dependent CYP3A4 inhibition risk

Cited by 3 publications

References 17 publications

Discovery of an Orally Bioavailable Benzimidazole Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor That Suppresses Body Weight Gain in Diet-Induced Obese Dogs and Postprandial Triglycerides in Humans

Discovery of an Orally Bioavailable Benzimidazole Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor That Suppresses Body Weight Gain in Diet-Induced Obese Dogs and Postprandial Triglycerides in Humans

N-Aryl-2-aminobenzimidazoles: Novel, Efficacious, Antimalarial Lead Compounds

Genotoxicity

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