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Discovery of novel S1P2 antagonists, part 3: Improving the oral bioavailability of a series of 1,3-bis(aryloxy)benzene derivatives.

Abstract：

:The structure of the S1P2 antagonist 1 has been modified with the aim of improving its oral bioavailability. The chemical modification of the alkyl chain and carboxylic acid moieties of 1 led to significant improvements in the oral exposure of compounds belonging to this series. The optimization of the ring size of the urea portion of these molecules also led to remarkable improvements in the oral exposure. Based on these changes, the pyrrolidine derivative 16 was identified as a suitable candidate compound and showed excellent pharmacokinetic profiles in rat and dog, while maintaining high levels of potency and selective antagonistic activity toward S1P2.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Kusumi K,Shinozaki K,Yamaura Y,Hashimoto A,Kurata H,Naganawa A,Otsuki K,Matsushita T,Sekiguchi T,Kakuuchi A,Yamamoto H,Seko T

doi

10.1016/j.bmcl.2016.01.031

subject

Has Abstract

pub_date

2016-02-15 00:00:00

pages

1209-13

issue

4

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(16)30031-2

journal_volume

26

pub_type

杂志文章

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