Synthesis, structure-activity relationship, and receptor pharmacology of a new series of quinoline derivatives acting as selective, noncompetitive mGlu1 antagonists.
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.
Mabire
Dominique
D
Department of Medicinal Chemistry, Johnson & Johnson Pharmaceutical Research & Development, a Division of Janssen-Cilag France, Campus de Maigremont, F-27106 Val de Reuil, France.
Coupa
Sophie
S
Adelinet
Christophe
C
Poncelet
Alain
A
Simonnet
Yvan
Y
Venet
Marc
M
Wouters
Ria
R
Lesage
Anne S J
AS
Van Beijsterveldt
Ludy
L
Bischoff
François
F
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
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