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

Abstract

We report the design and synthesis of a series of novel DGAT1 inhibitors in the benzimidazole class with a pyridyl-oxy-cyclohexanecarboxylic acid moiety. In particular, compound 11A is a potent DGAT1 inhibitor with excellent selectivity against ACAT1. Compound 11A significantly reduces triglyceride excursion in lipid tolerance tests (LTT) in both mice and dogs at low plasma exposure. An in vivo study in mice with des-fluoro analogue 10A indicates that this series of compounds appears to distribute in intestine preferentially over plasma. The propensity to target intestine over plasma could be advantageous in reducing potential side effects since lower circulating levels of drug are required for efficacy. However, in the preclinical species, compound 11A undergoes cis/trans epimerization in vivo, which could complicate further development due to the presence of an active metabolite. KEYWORDS: DGAT1, inhibitor, benzimidazole, ACAT1, cyclohexanecarboxylic acid, lipid tolerance test, epimerization, metabolite T ype II diabetes mellitus (T2DM) and obesity, two interlinked disease conditions, have emerged as the major threats to human health globally. 1,2 In 2008, World Health Organization estimated the number of overweight and obese adults worldwide to be 1 billion and 500 million, respectively. In 2009−2010, more than one-third of the American population was classified as obese. 3 Meanwhile, a recent estimate indicates that there are about 371 million people worldwide living with diabetes. 4 Current drugs available to treat diabetes and obesity have limitations in terms of longterm efficacy and/or side effects. 5−7 The unmet need prompts significant research efforts in this area.Inhibition of DGAT1 (diglyceride acyltransferase 1) has emerged as a potential mechanism for the treatment of T2DM and obesity. 8,9 The DGAT family (diglyce diglyceride acyltransferase 1 and 2) catalyzes the formation of triglyceride (TG) from diacylglycerol and acyl-CoA, the terminal and committed step in TG synthesis. 10 DGAT1 shares only limited sequence homology with DGAT2, the other known isoform. 11 In contrast, DGAT1 has more sequence homology to acyl CoA:cholesterol acyltransferase (ACAT1 and ACAT2). ACAT plays an important role in cholesterol homeostasis. 12 The strong interest in DGAT1 started after the reports on DGAT1 knockout mouse phenotyping studies. DGAT1 knockout mice were shown to be viable and resistant to diet-induced obesity. 13 Furthermore, these mice appeared to have increased sensitivity to insulin and leptin. 14 This compelling data set has inspired major efforts in identifying small molecule DGAT1 inhibitors for potential treatment of diabetes and obesity (Figure 1

Discovery of Orally Bioavailable Ligand Efficient Quinazolindiones as Potent and Selective Tankyrases Inhibitors

“…Moreover, compound 21 inhibits proliferation of A549 and H292 cell lines with IC 50 values of 39.5 and 12.8 nM, respectively. It is known that the of cyclohexane carboxylic acid can be epimerized via a plausible acyl-CoA mediated cis / trans isomerization through a cyclohexylidene (acyl-CoA) methanolate intermediate. , In this case, we also observed the epimerization of carboxylic acid of 21 in PK study. Interestingly, although the cis analogue of 21 is active in the enzymatic assays (TNKS1 and 2, IC 50 s of 316 and 100 nM, respectively), it shows poor cellular activity (IC 50 > 5 μM).…”

Positive regulation of prostate cancer cell growth by lipid droplet forming and processing enzymes DGAT1 and ABHD5

“…Thus targeting ABHD5 will further require understanding of this alternate function and presently limits a dual inhibition approach of both ABHD5 and DGAT1. However several DGAT1 inhibitors are being developed for treating obesity and other metabolic diseases [ 55 , 56 ], and some of these are in clinical trials [ 57 – 59 ]. Utilizing these available small molecule DGAT1 inhibitors in future studies will help assess their therapeutic feasibility in prostate cancer.…”

Microscale High-Throughput Experimentation as an Enabling Technology in Drug Discovery: Application in the Discovery of (Piperidinyl)pyridinyl-1H-benzimidazole Diacylglycerol Acyltransferase 1 Inhibitors

“…In reactions with electrophile 16, diversely functionalized nucleophiles were investigated including two pyrrolidines (20,21), a piperidinium chloride salt (22), a primary amine (23), an azetidinium chloride salt (24), and a spiropiperidine bearing a cyclic carbamate (25). Likewise, in reactions with nucleophile 4, diverse pyridyl fluorides were selected bearing ketone (26), acetamide (27), or iodide (29) functionality as well as different heterocycles (16,28,30). Both free bases and hydrochloride reagent salt forms (22,24) were included to better approximate the salt diversity of our compound collection, and we reasoned that the excess of base used would neutralize any acidic salts.…”

“…During our investigation of DGAT1 inhibitors, − we became interested in a series of benzimidazoles (Figure ). An early entry in the benzimidazole series ( 5 ) was synthesized via oxidative cyclization of diamine 1 with 2-chloronicotinaldehyde ( 2 ) to generate 3 .…”