title: Discovery of OT4003, a novel, potent, and orally active cys-LT1 receptor antagonist.
abstract: The present paper describes the structural modifications leading to the discovery of a new series of quinoline-containing cys-LT1 receptor (LTD4 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-(3-(2-(7- chloroquinolin-2-yl)ethenyl)phenylaminomethyl)-phenoxyl++ +-hexanoic acid) was found to be a potent and selective inhibitor of [3H]LTD4 specific binding to guinea pig lung membranes (IC50 2.4 +/- 1.0 nM), and also a potent, orally active, antagonist of LTD4 induced bronchoconstriction in guinea pigs [ED50 0.14 (ED16 0.1-ED84 0.4) mg/kg; 4 h pretreatment]. The enantiomerically pure OT4003 was prepared using a short convergent synthesis, including an enzymatic resolution step.
authors.affiliation: Department of Chemistry, Leo Pharmaceutical Products, Ballerup, Denmark.
authors.forename: O
authors.initials: O
authors.lastname: Tvaermose-Nielsen
authors.forename: S
authors.initials: S
authors.lastname: Rachlin
authors.forename: H
authors.initials: H
authors.lastname: Dannacher
authors.forename: F
authors.initials: F
authors.lastname: Björkling
authors.forename: D
authors.initials: D
authors.lastname: Kirstein
authors.forename: E
authors.initials: E
authors.lastname: Bramm
authors.forename: C K
authors.initials: CK
authors.lastname: Nielsen
authors.forename: J T
authors.initials: JT
authors.lastname: Mortensen
authors.forename: L
authors.initials: L
authors.lastname: Binderup
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002208:Caproates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D020024:Leukotriene Antagonists; D017998:Leukotriene D4 / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins; D051379:Mice; D008830:Microbodies / Q000187:drug effects; D011804:Quinolines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D018077:Receptors, Leukotriene; D013329:Structure-Activity Relationship; D014316:Tritium
chemical_list: D002208:Caproates; D020024:Leukotriene Antagonists; D008565:Membrane Proteins; C105917:OT 4003; D011804:Quinolines; D018077:Receptors, Leukotriene; D014316:Tritium; D017998:Leukotriene D4; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor