Himbacine-Derived Thrombin Receptor Antagonists: C₇‑Aminomethyl and C_9a-Hydroxy Analogues of Vorapaxar

We have synthesized several C₇-aminomethyl analogues of vorapaxar that are potent PAR-1 antagonists. Many of these analogues showed excellent in vitro binding affinity and pharmacokinetics profile in rats. Compound <b>6a</b> from this series showed excellent PAR-1 activity (<i>K</i>_i = 5 nM). We have also synthesized a C_9a-hydroxy analogue of vorapaxar, which showed very good PAR-1 affinity (<i>K</i>_i = 19.5 nM) along with excellent rat pharmacokinetic profile and ex vivo efficacy in the cynomolgus monkey

Himbacine-Derived Thrombin Receptor Antagonists: C₇‑Spirocyclic Analogues of Vorapaxar

We have synthesized several C₇-spirocyclic analogues of vorapaxar and evaluated their in vitro activities against PAR-1 receptor. Some of these analogues showed activities and rat plasma levels comparable to vorapaxar. Compound <b>5c</b> from this series showed excellent PAR-1 activity (<i>K</i>_i = 5.1 nM). We also present a model of these spirocyclic compounds docked to the PAR-1 receptor based on the X-ray crystal structure of vorapaxar bound to PAR-1 receptor. This model explains some of the structure–activity relationships in this series

Design, Synthesis, and Evaluation of Novel and Selective G‑protein Coupled Receptor 120 (GPR120) Spirocyclic Agonists

Type 2 diabetes mellitus (T2DM) is an ever increasing worldwide epidemic, and the identification of safe and effective insulin sensitizers, absent of weight gain, has been a long-standing goal of diabetes research. G-protein coupled receptor 120 (GPR120) has recently emerged as a potential therapeutic target for treating T2DM. Natural occurring, and more recently, synthetic agonists have been associated with insulin sensitizing, anti-inflammatory, and fat metabolism effects. Herein we describe the design, synthesis, and evaluation of a novel spirocyclic GPR120 agonist series, which culminated in the discovery of potent and selective agonist <b>14</b>. Furthermore, compound <b>14</b> was evaluated <i>in vivo</i> and demonstrated acute glucose lowering in an oral glucose tolerance test (oGTT), as well as improvements in homeostatic measurement assessment of insulin resistance (HOMA-IR; a surrogate marker for insulin sensitization) and an increase in glucose infusion rate (GIR) during a hyperinsulinemic euglycemic clamp in diet-induced obese (DIO) mice