2. Academic Validation
  3. 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

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

Affiliation

  • 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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