Discovery of novel tricyclic full agonists for the G-protein-coupled niacin receptor 109A with minimized flushing in rats

  • J Med Chem. 2009 Apr 23;52(8):2587-602. doi: 10.1021/jm900151e.
Hong C Shen  1 ,  Fa-Xiang Ding ,  Qiaolin Deng ,  Larissa C Wilsie ,  Mihajlo L Krsmanovic ,  Andrew K Taggart ,  Ester Carballo-Jane ,  Ning Ren ,  Tian-Quan Cai ,  Tsuei-Ju Wu ,  Kenneth K Wu ,  Kang Cheng ,  Qing Chen ,  Michael S Wolff ,  Xinchun Tong ,  Tom G Holt ,  M Gerard Waters ,  Milton L Hammond ,  James R Tata ,  Steven L Colletti
Affiliations
  • 1. Departments of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., Rahway, New Jersey 07065-0900, USA. [email protected]
PMID: 19309152 DOI: 10.1021/jm900151e
Abstract

Tricyclic analogues were rationally designed as the high affinity niacin receptor G-protein-coupled receptor 109A (GPR109A) agonists by overlapping three lead structures. Various tricyclic anthranilide and cycloalkene carboxylic acid full agonists were discovered with excellent in vitro activity. Compound 2g displayed a good therapeutic index regarding free Fatty Acids (FFA) reduction and vasodilation effects in rats, with very weak Cytochrome P450 2C8 (CYP2C8) and Cytochrome P450 2C9 (CYP2C9) inhibition, and a good mouse pharmacokinetics (PK) profile.