3-Cyano-5-fluoro-N-arylbenzamides as negative allosteric modulators of mGlu(5): Identification of easily prepared tool compounds with CNS exposure in rats.
Development of SAR in a 3-cyano-5-fluoro-N-arylbenzamide series of non-competitive antagonists of mGlu(5) using a functional cell-based assay is described in this Letter. Further characterization of selected potent compounds in in vitro assays designed to measure their metabolic stability and protein binding is also presented. Subsequent evaluation of two new compounds in pharmacokinetic studies using intraperitoneal dosing in rats demonstrated good exposure in both plasma and brain samples.
Felts
Andrew S
AS
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Lindsley
Stacey R
SR
Lamb
Jeffrey P
JP
Rodriguez
Alice L
AL
Menon
Usha N
UN
Jadhav
Satyawan
S
Jones
Carrie K
CK
Conn
P Jeffrey
PJ
Lindsley
Craig W
CW
Emmitte
Kyle A
KA
D000494:Allosteric Regulation; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
D001549:Benzamides; D001798:Blood Proteins; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate