1622180-53-3Relevant articles and documents
OXIME ETHER COMPOUNDS
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, (2019/02/25)
Disclosed are compounds of Formula (I): (I) or a salt thereof, wherein: X is CH or N; Y is CH or N; R1 is -OH or -OP(O)(OH)2; L1 is -CR3=N-O-CRaRa- or CRaR-O-N=CR3; L
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.
, (2019/03/19)
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.
SUBSTITUTED BICYCLIC COMPOUNDS
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, (2016/03/13)
Disclosed are compounds of Formulas (I), (II), (III), (IV), and (V) and/or a salt thereof, wherein R1 is OH or OP(O)(OH)2, and X1, X2, X3, R2, R2a, Ra, Rb, and Rc are defined herein. Also disclosed are methods of using such compounds as selective agonists for G protein coupled receptor S1P1, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.
Asymmetric Hydroboration Approach to the Scalable Synthesis of ((1R,3S)-1-Amino-3-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methanol (BMS-986104) as a Potent S1P1 Receptor Modulator
Yang, Michael G.,Xiao, Zili,Dhar, T. G. Murali,Xiao, Hai-Yun,Gilmore, John L.,Marcoux, David,Xie, Jenny H.,McIntyre, Kim W.,Taylor, Tracy L.,Borowski, Virna,Heimrich, Elizabeth,Li, Yu-Wen,Feng, Jianlin,Fernandes, Alda,Yang, Zheng,Balimane, Praveen,Marino, Anthony M.,Cornelius, Georgia,Warrack, Bethanne M.,Mathur, Arvind,Wu, Dauh-Rurng,Li, Peng,Gupta, Anuradha,Pragalathan, Bala,Shen, Ding Ren,Cvijic, Mary Ellen,Lehman-Mckeeman, Lois D.,Salter-Cid, Luisa,Barrish, Joel C.,Carter, Percy H.,Dyckman, Alaric J.
, p. 11138 - 11147 (2016/12/30)
We describe a highly efficient route for the synthesis of 4a (BMS-986104). A key step in the synthesis is the asymmetric hydroboration of trisubstituted alkene 6. Particularly given the known difficulties involved in this type of transformation (6 → 7), the current methodology provides an efficient approach to prepare this class of compounds. In addition, we disclose the efficacy of 4a in a mouse EAE model, which is comparable to 4c (FTY720). Mechanistically, 4a exhibited excellent remyelinating effects on lysophosphatidylcholine (LPC) induced demyelination in a three-dimensional brain cell culture assay.
BICYCLIC COMPOUNDS
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, (2014/09/03)
Disclosed are compounds of Formula (I) and/or a salt thereof; wherein R is —OH or —OP(O)(OH)2. Also disclosed are methods of using such compounds as selective agonists for G protein-coupled receptor S1P1, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.
