| Literature DB >> 32944145 |
Zili Xiao1, Michael G Yang1, T G Murali Dhar1, Hai-Yun Xiao1, John L Gilmore1, David Marcoux1, Kim W McIntyre1, Tracy L Taylor1, Hong Shi1, Paul C Levesque1, Anthony M Marino1, Georgia Cornelius1, Arvind Mathur1, Ding Ren Shen1, Mary Ellen Cvijic1, Lois D Lehman-McKeeman1, Huadong Sun1, Jenny H Xie1, Percy H Carter1, Alaric J Dyckman1.
Abstract
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 S1P1 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 (ED50 < 0.05 mg/kg) and predicted human half-life (t 1/2 ∼ 5 days).Entities:
Year: 2020 PMID： 32944145 PMCID： PMC7488280 DOI： 10.1021/acsmedchemlett.0c00333
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345