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

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

Affiliation

  • 1 Departments of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., Rahway, New Jersey 07065-0900, USA. hong_shen@merck.com
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.

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