title: 3-[Substituted]-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitriles: identification of highly potent and selective metabotropic glutamate subtype 5 receptor antagonists.
abstract: Structure-activity relationship studies on the phenyl ring of 3-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile 2 led to the discovery that small, non-hydrogen bond donor substituents at the 3-position led to a substantial increase in in vitro potency. In particular, 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (7) is a highly potent and selective mGlu5 receptor antagonist with good rat pharmacokinetics, brain penetration, and in vivo receptor occupancy.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121-1140, USA.
authors.forename: Lida R
authors.initials: LR
authors.lastname: Tehrani
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Smith
authors.forename: Dehua
authors.initials: D
authors.lastname: Huang
authors.forename: Steve F
authors.initials: SF
authors.lastname: Poon
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Roppe
authors.forename: Thomas Jon
authors.initials: TJ
authors.lastname: Seiders
authors.forename: Deborah F
authors.initials: DF
authors.lastname: Chapman
authors.forename: Janice
authors.initials: J
authors.lastname: Chung
authors.forename: Merryl
authors.initials: M
authors.lastname: Cramer
authors.forename: Nicholas D P
authors.initials: ND
authors.lastname: Cosford
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry* / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry*; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013777:Tetrazoles / Q000737:chemistry*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D009570:Nitriles; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013777:Tetrazoles; C014356:benzonitrile