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3-[Substituted]-5-(5-pyridin-2-yl-2 H-tetrazol-2-yl)benzonitriles: Identification of highly potent and selective metabotropic glutamate subtype 5 receptor antagonists

Structure–activity relationship studies on the phenyl ring of 3-(5-pyridin-2-yl-2 H-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-2 H-te...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2005-11, Vol.15 (22), p.5061-5064
Main Authors: Tehrani, Lida R., Smith, Nicholas D., Huang, Dehua, Poon, Steve F., Roppe, Jeffrey R., Seiders, Thomas Jon, Chapman, Deborah F., Chung, Janice, Cramer, Merryl, Cosford, Nicholas D.P.
Format: Article
Language:English
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Summary:Structure–activity relationship studies on the phenyl ring of 3-(5-pyridin-2-yl-2 H-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-2 H-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. Structure–activity relationship studies on the phenyl ring of 3-(5-pyridin-2-yl-2 H-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-2 H-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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2005.07.062