Potent DGAT1 Inhibitors in the Benzimidazole Class with a Pyridyl-oxy-cyclohexanecarboxylic Acid Moiety

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Drug Discovery

Background:

• Diacylglycerol acyltransferase 1 (DGAT1) is a key enzyme in triglyceride synthesis.
• Inhibiting DGAT1 is a therapeutic strategy for metabolic disorders.
• Benzimidazole scaffolds offer a promising structural class for DGAT1 inhibitor development.

Purpose of the Study:

• To design and synthesize novel DGAT1 inhibitors based on a benzimidazole core.
• To evaluate the potency, selectivity, and in vivo efficacy of these inhibitors.
• To investigate the pharmacokinetic profile and potential metabolic liabilities of the lead compounds.

Main Methods:

• Synthesis of a series of benzimidazole derivatives incorporating a pyridyl-oxy-cyclohexanecarboxylic acid moiety.
• In vitro enzyme inhibition assays to determine DGAT1 and ACAT1 activity.
• In vivo lipid tolerance tests (LTT) in mice and dogs to assess triglyceride reduction.
• Pharmacokinetic studies in mice to determine tissue distribution (intestine vs. plasma).

Main Results:

• Compound 11A demonstrated potent DGAT1 inhibition with high selectivity over ACAT1.
• Compound 11A significantly reduced postprandial triglyceride levels in both mice and dogs at low doses.
• In vivo studies indicated preferential distribution of analogues (e.g., 10A) to the intestine over plasma.
• Compound 11A exhibited cis/trans epimerization in preclinical species, forming an active metabolite.

Conclusions:

• The novel benzimidazole series, particularly compound 11A, represents a promising class of DGAT1 inhibitors.
• Preferential intestinal distribution suggests a potential for reduced systemic side effects.
• The observed in vivo epimerization of compound 11A requires further investigation for successful drug development.