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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.
Gilmore, John L; Xiao, Hai-Yun; Dhar, T G Murali; Yang, Michael G; Xiao, Zili; Xie, Jenny; Lehman-McKeeman, Lois D; Gong, Lei; Sun, Huadong; Lecureux, Lloyd; Chen, Cliff; Wu, Dauh-Rurng; Dabros, Marta; Yang, Xiaoxia; Taylor, Tracy L; Zhou, Xia D; Heimrich, Elizabeth M; Thomas, Rochelle; McIntyre, Kim W; Borowski, Virna; Warrack, Bethanne M; Li, Yuwen; Shi, Hong; Levesque, Paul C; Yang, Zheng; Marino, Anthony M; Cornelius, Georgia; D'Arienzo, Celia J; Mathur, Arvind; Rampulla, Richard; Gupta, Anuradha; Pragalathan, Bala; Shen, Ding Ren; Cvijic, Mary Ellen; Salter-Cid, Luisa M; Carter, Percy H; Dyckman, Alaric J.
Afiliación
  • Gilmore JL; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Xiao HY; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Dhar TGM; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Yang MG; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Xiao Z; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Xie J; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Lehman-McKeeman LD; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Gong L; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Sun H; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Lecureux L; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Chen C; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Wu DR; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Dabros M; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Yang X; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Taylor TL; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Zhou XD; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Heimrich EM; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Thomas R; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • McIntyre KW; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Borowski V; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Warrack BM; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Li Y; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Shi H; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Levesque PC; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Yang Z; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Marino AM; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Cornelius G; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • D'Arienzo CJ; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Mathur A; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Rampulla R; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Gupta A; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Pragalathan B; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Shen DR; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Cvijic ME; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Salter-Cid LM; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Carter PH; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
  • Dyckman AJ; Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543-4000 , United States.
J Med Chem ; 62(5): 2265-2285, 2019 03 14.
Article en En | MEDLINE | ID: mdl-30785748
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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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Tetrahidronaftalenos / Ensayos Clínicos como Asunto / Receptores de Esfingosina-1-Fosfato / Naftalenos Tipo de estudio: Diagnostic_studies Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2019 Tipo del documento: Article
Texto completo
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Tetrahidronaftalenos / Ensayos Clínicos como Asunto / Receptores de Esfingosina-1-Fosfato / Naftalenos Tipo de estudio: Diagnostic_studies Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2019 Tipo del documento: Article