Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition and for the treatment of B cell related diseases. We report a series of compounds based on 8-amino-imidazo[1,5-a]pyrazine that are potent reversible BTK inhibitors with excellent kinase selectivity. Selectivity is achieved through specific interactions of the ligand with the kinase hinge and driven by aminopyridine hydrogen bondings with Ser538 and Asp539, and by hydrophobic interaction of trifluoropyridine in the back pocket. These interactions are evident in the X-ray crystal structure of the lead compounds 1 and 3 in the complex with the BTK enzyme. Our lead compounds show desirable PK profiles and efficacy in the preclinical rat collagen induced arthritis model.

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ABSTRACT:We report the discovery of a novel series of DGAT1 inhibitors in the benzimidazole class with a piperdinyl-oxy-cyclohexanecarboxylic acid moiety. This novel series possesses significantly improved selectivity against the A 2A receptor, no ACAT1 offtarget activity at 10 μM, and higher aqueous solubility and free fraction in plasma as compared to the previously reported pyridyl-oxy-cyclohexanecarboxylic acid series. In particular, 5B was shown to possess an excellent selectivity profile by screening it against a panel of more than 100 biological targets. Compound 5B significantly reduces lipid excursion in LTT in mouse and rat, demonstrates DGAT1 mediated reduction of food intake and body weight in mice, is negative in a 3-strain Ames test, and appears to distribute preferentially in the liver and the intestine in mice. We believe this lead series possesses significant potential to identify optimized compounds for clinical development. KEYWORDS: DGAT1, inhibitor, benzimidazole, ACAT1, A 2A receptor, cyclohexanecarboxylic acid, lipid tolerance test, epimerization, metabolite, Ames test, skin DGAT1 inhibitors have emerged as potential therapeutic agents against diabetes and obesity. 1 DGAT (acyl CoA:diacylglycerol acyltransferase) catalyzes the final and committed step in the synthesis of triglyceride: the formation of triacylglycerol from diacylglycerol and acyl-CoA. DGAT1 is one of the isoforms and shares only limited homology with DGAT2 in the terms of amino acid sequence. 2−4 DGAT1 has more sequence homology to acyl CoA:cholesterol acyltransferase (ACAT1 and ACAT2), which play a crucial role in cholesterol homeostasis. 5 DGAT1 has attracted much attention since the disclosure of the phenotype of DGAT1 knockout mice, which were shown to be viable and resistant to diet-induced obesity. 6 DGAT1 knockout mice were also reported to have enhanced insulin sensitivity compared to wild-type mice. 7 The data, taken together, has prompted significant research effort in identifying small molecule DGAT1 inhibitors as a potential treatment for obesity and diabetes (Figure 1) 8−16 In a phase II clinical trial, 3-week dosing of LCQ-908 (pradigastat) at 20 mg daily resulted in a 40% reduction in fasting triglyceride levels in patients with familial chylomicronemia syndrome, thus demonstrating the clinical proof of concept that inhibition of DGAT1 in humans leads to reductions of plasma triglycerides. 17 Recent reports on the clinical results for AZD-7687 demonstrated the ability of DGAT1 inhibitors to attenuate postprandial triacylglyceride excursion. However, the gastrointestinal side effects could hinder further development of DGAT1 inhibitors as a novel treatment for diabetes and obesity. 18,19 Recently, we disclosed a series of novel DGAT1 inhibitors in the benzimidazole class bearing a pyridyl-oxy-cyclohexanecarboxylic acid moiety. 20 A representative of this series, 1A, is a potent DGAT1 inhibitor with excellent selectivity against

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