Open AccessAryl Ether-Derived Sphingosine-1-Phosphate Receptor (S1P1) Modulators: Optimization of the PK, PD, and Safety Profiles
Author(s) -
Zili Xiao,
Michael G. Yang,
T. G. Murali Dhar,
Hai-Yun Xiao,
John L. Gilmore,
David Marcoux,
Kim W. McIntyre,
Tracy Taylor,
Hong Shi,
Paul Lévesque,
Anthony M. Marino,
Georgia Cornelius,
Arvind Mathur,
Ding Ren Shen,
Mary Ellen Cvijic,
Lois D. LehmanMcKeeman,
Huadong Sun,
Jenny Xie,
Percy H. Carter,
Alaric J. Dyckman
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00333
Subject(s) - potency , ether , in vivo , aryl , pharmacology , ligand efficiency , chemistry , thioether , ed50 , combinatorial chemistry , stereochemistry , in vitro , ligand (biochemistry) , receptor , medicine , biochemistry , biology , organic chemistry , alkyl , microbiology and biotechnology
Efforts aimed at increasing the in vivo potency and reducing the elimination half-life of 1 and 2 led to the identification of aryl ether and thioether-derived bicyclic S1P 1 differentiated modulators 3 - 6 . The effects of analogs 3 - 6 on lymphocyte reduction in the rat (desired pharmacology) along with pulmonary- and cardiovascular-related effects (undesired pharmacology) are described. Optimization of the overall properties in the aryl ether series yielded 3d , and the predicted margin of safety against the cardiovascular effects of 3d would be large enough for human studies. Importantly, compared to 1 and 2 , compound 3d had a better profile in both potency (ED 50 < 0.05 mg/kg) and predicted human half-life ( t 1/2 ∼ 5 days).