Discovery of highly potent, selective, orally bioavailable, metabotropic glutamate subtype 5 (mGlu5) receptor antagonists devoid of cytochrome P450 1A2 inhibitory activity.
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.
Smith
Nicholas D
ND
Department of Medicinal Chemistry, Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA. nicholas_smith@merck.com
Poon
Steve F
SF
Huang
Dehua
D
Green
Mitchell
M
King
Christopher
C
Tehrani
Lida
L
Roppe
Jeffrey R
JR
Chung
Janice
J
Chapman
Deborah P
DP
Cramer
Merryl
M
Cosford
Nicholas D P
ND
D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D001682:Biological Availability; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*
D014151:Anti-Anxiety Agents; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013777:Tetrazoles