Discovery of highly potent, selective, orally bioavailable, metabotropic glutamate subtype 5 (mGlu5) receptor antagonists devoid of cytochrome P450 1A2 inhibitory activity

Nicholas D Smith; Steve F Poon; Dehua Huang; Mitchell Green; Christopher King; Lida Tehrani; Jeffrey R Roppe; Janice Chung; Deborah P Chapman; Merryl Cramer; Nicholas D P Cosford

doi:10.1016/j.bmcl.2004.09.018

Discovery of highly potent, selective, orally bioavailable, metabotropic glutamate subtype 5 (mGlu5) receptor antagonists devoid of cytochrome P450 1A2 inhibitory activity

Bioorg Med Chem Lett. 2004 Nov 15;14(22):5481-4. doi: 10.1016/j.bmcl.2004.09.018.

Authors

Nicholas D Smith¹, Steve F Poon, Dehua Huang, Mitchell Green, Christopher King, Lida Tehrani, Jeffrey R Roppe, Janice Chung, Deborah P Chapman, Merryl Cramer, Nicholas D P Cosford

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA. [email protected]

PMID: 15482908
DOI: 10.1016/j.bmcl.2004.09.018

Abstract

Structure-activity relationship studies focused on bio-isosteric replacements of 2-pyridyl resulted in mGlu5 receptor antagonists with reduced inhibition of cytochrome P450 1A2. This led to highly potent, selective and orally bioavailable 2-imidazolyl tetrazoles such as (10) that are devoid of cytochrome P450 inhibitory activity.

MeSH terms

Administration, Oral
Animals
Anti-Anxiety Agents / chemical synthesis
Anti-Anxiety Agents / chemistry
Anti-Anxiety Agents / pharmacokinetics
Biological Availability
Cytochrome P-450 CYP1A2 Inhibitors*
Molecular Structure
Rats
Rats, Sprague-Dawley
Receptor, Metabotropic Glutamate 5
Receptors, Metabotropic Glutamate / antagonists & inhibitors*
Structure-Activity Relationship
Tetrazoles / chemical synthesis*
Tetrazoles / chemistry
Tetrazoles / pharmacokinetics*

Substances

Anti-Anxiety Agents
Cytochrome P-450 CYP1A2 Inhibitors
Receptor, Metabotropic Glutamate 5
Receptors, Metabotropic Glutamate
Tetrazoles