title: Synthesis, structure-activity relationship, and receptor pharmacology of a new series of quinoline derivatives acting as selective, noncompetitive mGlu1 antagonists.
abstract: We describe the discovery and the structure-activity relationship of a new series of quinoline derivatives acting as selective and highly potent noncompetitive mGlu1 antagonists. We first identified cis-10 as a fairly potent mGlu1 antagonist (IC(50) = 20 nM) in a cell-based signal transduction assay on the rat mGlu1 receptor expressed in CHO-K1 cells, and then we were able to design and synthesize highly potent compounds on both rat and human mGlu1 receptors as exemplified by compound cis-64a, which has an antagonist potency of 0.5 nM for the human mGlu1 receptor. We briefly present and discuss the in vitro metabolic stability of the compounds in human liver microsomes. We finally report the pharmacokinetic properties of our lead compound cis-64a.
authors.affiliation: Department of Medicinal Chemistry, Johnson & Johnson Pharmaceutical Research & Development, a Division of Janssen-Cilag France, Campus de Maigremont, F-27106 Val de Reuil, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Mabire
authors.forename: Sophie
authors.initials: S
authors.lastname: Coupa
authors.forename: Christophe
authors.initials: C
authors.lastname: Adelinet
authors.forename: Alain
authors.initials: A
authors.lastname: Poncelet
authors.forename: Yvan
authors.initials: Y
authors.lastname: Simonnet
authors.forename: Marc
authors.initials: M
authors.lastname: Venet
authors.forename: Ria
authors.initials: R
authors.lastname: Wouters
authors.forename: Anne S J
authors.initials: AS
authors.lastname: Lesage
authors.forename: Ludy
authors.initials: L
authors.lastname: Van Beijsterveldt
authors.forename: François
authors.initials: F
authors.lastname: Bischoff
mesh_terms: D000818:Animals; D001682:Biological Availability; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D007424:Intracellular Fluid / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D011804:Quinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C500081:3,4-dihydro-2H-pyrano(2,3-b)quinolin-7-yl 4-methoxycyclohexyl ketone; D011804:Quinolines; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D002118:Calcium