Identification and Preclinical Pharmacology of ((1 R,3 S)-1-Amino-3-(( S)-6-(2-methoxyphenethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methanol (BMS-986166): A Differentiated Sphingosine-1-phosphate Receptor 1 (S1P1) Modulator Advanced into Clinical Trials

  • J Med Chem. 2019 Mar 14;62(5):2265-2285. doi: 10.1021/acs.jmedchem.8b01695.
John L Gilmore  1 ,  Hai-Yun Xiao  1 ,  T G Murali Dhar  1 ,  Michael G Yang  1 ,  Zili Xiao  1 ,  Jenny Xie  1 ,  Lois D Lehman-McKeeman  1 ,  Lei Gong  1 ,  Huadong Sun  1 ,  Lloyd Lecureux  1 ,  Cliff Chen  1 ,  Dauh-Rurng Wu  1 ,  Marta Dabros  1 ,  Xiaoxia Yang  1 ,  Tracy L Taylor  1 ,  Xia D Zhou  1 ,  Elizabeth M Heimrich  1 ,  Rochelle Thomas  1 ,  Kim W McIntyre  1 ,  Virna Borowski  1 ,  Bethanne M Warrack  1 ,  Yuwen Li  1 ,  Hong Shi  1 ,  Paul C Levesque  1 ,  Zheng Yang  1 ,  Anthony M Marino  1 ,  Georgia Cornelius  1 ,  Celia J D'Arienzo  1 ,  Arvind Mathur  1 ,  Richard Rampulla  1 ,  Anuradha Gupta  1 ,  Bala Pragalathan  1 ,  Ding Ren Shen  1 ,  Mary Ellen Cvijic  1 ,  Luisa M Salter-Cid  1 ,  Percy H Carter  1 ,  Alaric J Dyckman  1
Affiliations
  • 1. Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
PMID: 30785748 DOI: 10.1021/acs.jmedchem.8b01695
Abstract

Recently, our research group reported the identification of BMS-986104 (2) as a differentiated S1P1 receptor modulator. In comparison to fingolimod (1), a full agonist of S1P1 currently marketed for the treatment of relapse remitting Multiple Sclerosis (RRMS), 2 offers several potential advantages having demonstrated improved safety multiples in preclinical evaluations against undesired pulmonary and cardiovascular effects. In clinical trials, 2 was found to exhibit a pharmacokinetic half-life ( T1/2) longer than that of 1, as well as a reduced formation of the phosphate metabolite that is required for activity against S1P1. Herein, we describe our efforts to discover highly potent, partial agonists of S1P1 with a shorter T1/2 and increased in vivo phosphate metabolite formation. These efforts culminated in the discovery of BMS-986166 (14a), which was advanced to human clinical evaluation. The pharmacokinetic/pharmacodynamic (PK/PD) relationship as well as pulmonary and cardiovascular safety assessments are discussed. Furthermore, efficacy of 14a in multiple preclinical models of autoimmune diseases are presented.

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