Discovery of OT4003, a novel, potent, and orally active cys-LT 1 receptor antagonist

Abstract

The present paper describes the structural modifications leading to the discovery of a new series of quinoline-containing cys-LT 1 receptor (LTD 4 receptor) antagonists. A structural optimization with respect to the in vitro receptor binding, the in vivo brochoconstriction, and the toxicological effect in the form of peroxisomal proliferation was performed in order to achieve the target compound OT4003. OT4003 (( S)-(+)- E-2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl)phenoxy]-hexanoic acid) was found to be a potent and selective inhibitor of [ 3H]LTD 4 specific binding to guinea pig lung membranes (IC 50 2.4±1.0 nM), and also a potent, orally active, antagonist of LTD 4 induced bronchoconstriction in guinea pigs [Ed 50 0.14 (ED 16 0.1−ED 84 0.4) mg/kg; 4 h pretreatment]. The enantiomerically pure OT4003 was prepared using a short convergent synthesis, including an enzymatic resolution step.