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Synthesis and evaluation of prodrugs of corticotropin-releasing factor-1 (CRF1) receptor antagonist BMS-665053 leading to improved oral bioavailability.

Abstract：

:A series of phosphate and ester-based prodrugs of anilinopyrazinone 1 (BMS-665053) containing either a methylene or an (acyloxy)alkoxy linker was prepared and evaluated in rat pharmacokinetic studies with the goal of improving the oral bioavailability of the parent (1). The prodrugs, in general, had improved aqueous solubility and oral bioavailability compared to 1. Prodrug 12, which contains an (acyloxy)alkoxy linker, showed the greatest improvement in the oral bioavailability relative to the parent (1), with a seven-fold increase (from 5% to 36%) in rat pharmacokinetic studies.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Hartz RA,Vrudhula VM,Ahuja VT,Grace JE,Lodge NJ,Bronson JJ,Macor JE

doi

10.1016/j.bmcl.2017.02.015

subject

Has Abstract

pub_date

2017-03-15 00:00:00

pages

1360-1363

issue

6

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(17)30137-3

journal_volume

27

pub_type

杂志文章

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