Discovery of a Potent and Selective DGAT1 Inhibitor with a Piperidinyl-oxy-cyclohexanecarboxylic Acid Moiety

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 off-target 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, <b>5B</b> was shown to possess an excellent selectivity profile by screening it against a panel of more than 100 biological targets. Compound <b>5B</b> 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

Investigation of Cardiovascular Effects of Tetrahydro-β-carboline sstr3 antagonists

Antagonism of somatostatin subtype receptor 3 (sstr3) has emerged as a potential treatment of Type 2 diabetes. Unfortunately, the development of our first preclinical candidate, MK-4256, was discontinued due to a dose-dependent QTc (QT interval corrected for heart rate) prolongation observed in a conscious cardiovascular (CV) dog model. As the fate of the entire program rested on resolving this issue, it was imperative to determine whether the observed QTc prolongation was associated with hERG channel (the protein encoded by the human Ether-à-go-go-Related Gene) binding or was mechanism-based as a result of antagonizing sstr3. We investigated a structural series containing carboxylic acids to reduce the putative hERG off-target activity. A key tool compound, <b>3A</b>, was identified from this SAR effort. As a potent sstr3 antagonist, <b>3A</b> was shown to reduce glucose excursion in a mouse oGTT assay. Consistent with its minimal hERG activity from in vitro assays, <b>3A</b> elicited little to no effect in an anesthetized, vagus-intact CV dog model at high plasma drug levels. These results afforded the critical conclusion that sstr3 antagonism is not responsible for the QTc effects and therefore cleared a path for the program to progress

Discovery of MK-1421, a Potent, Selective sstr3 Antagonist, as a Development Candidate for Type 2 Diabetes

The imidazolyl-tetrahydro-β-carboline class of sstr3 antagonists have demonstrated efficacy in a murine model of glucose excursion and may have potential as a treatment for type 2 diabetes. The first candidate in this class caused unacceptable QTc interval prolongation in oral, telemetrized cardiovascular (CV) dogs. Herein, we describe our efforts to identify an acceptable candidate without CV effects. These efforts resulted in the identification of (1<i>R</i>,3<i>R</i>)-3-(4-(5-fluoropyridin-2-yl)-1<i>H</i>-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-1-(3-methyl-1,3,4-oxadiazol-3<i>H</i>-2-one-5-yl)-2,3,4,9-tetrahydro-1<i>H</i>-β-carboline (<b>17e</b>, MK-1421)

The Discovery of MK-4256, a Potent SSTR3 Antagonist as a Potential Treatment of Type 2 Diabetes

A structure–activity relationship study of the imidazolyl-β-tetrahydrocarboline series identified MK-4256 as a potent, selective SSTR3 antagonist, which demonstrated superior efficacy in a mouse oGTT model. MK-4256 reduced glucose excursion in a dose-dependent fashion with maximal efficacy achieved at doses as low as 0.03 mg/kg po. As compared with glipizide, MK-4256 showed a minimal hypoglycemia risk in mice