Identification of potent tricyclic prodrug S1P1 receptor modulators

被引：5

作者：

Marcoux, David ^{[1
]}

Xiao, Hai-Yun ^{[1
]}

Dhar, T. G. Murali ^{[1
]}

Xie, Jenny ^{[1
]}

Lehman-McKeeman, Lois D. ^{[1
]}

Wu, Dauh-Rurng ^{[1
]}

Dabros, Marta ^{[1
]}

Yang, Xiaoxia ^{[1
]}

Taylor, Tracy L. ^{[1
]}

Zhou, Xia D. ^{[1
]}

Heimrich, Elizabeth M. ^{[1
]}

Thomas, Rochelle ^{[1
]}

McIntyre, Kim W. ^{[1
]}

Shi, Hong ^{[1
]}

Levesque, Paul C. ^{[1
]}

Sun, Huadong ^{[1
]}

Yang, Zheng ^{[1
]}

Marino, Anthony M. ^{[1
]}

Cornelius, Georgia ^{[1
]}

D'Arienzo, Celia J. ^{[1
]}

Gupta, Anuradha ^{[2
]}

Pragalathan, Bala ^{[2
]}

Rampulla, Richard ^{[1
]}

Mathur, Arvind ^{[1
]}

Shen, Ding Ren ^{[1
]}

Cvijic, Mary Ellen ^{[1
]}

Salter-Cid, Luisa ^{[1
]}

Lombardo, Louis J. ^{[1
]}

Carter, Percy H. ^{[1
]}

Dyckman, Alaric J. ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, Princeton, NJ 08543 USA

[2] BMS Biocon Res Ctr, Bangalore, Karnataka, India

来源：

MEDCHEMCOMM | 2017年 / 8卷 / 04期

关键词：

CROSS-COUPLING REACTIONS; ORAL FINGOLIMOD FTY720; SPHINGOSINE; 1-PHOSPHATE; MULTIPLE-SCLEROSIS; AGONISTS; SPHINGOSINE-1-PHOSPHATE; DISCOVERY;

D O I：

10.1039/c6md00539j

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Recently, our research group reported the identification of prodrug amino-alcohol 2 as a potent and efficacious S1P(1) receptor modulator. This molecule is differentiated preclinically over the marketed drug fingolimod (Gilenya 1), whose active phosphate metabolite is an S1P(1) full agonist, in terms of pulmonary and cardiovascular safety. S1P(1) partial agonist 2, however, has a long half-life in rodents and was projected to have a long half-life in humans. The purpose of this communication is to disclose highly potent partial agonists of S1P(1) with shorter half-lives relative to the clinical compound 2. PK/PD relationships as well as their preclinical pulmonary and cardiovascular safety assessment are discussed.

引用

页码：725 / 729

页数：5

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