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.
Department of Medicinal Chemistry, Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA. nicholas_smith@merck.com
Nicholas D
ND
Smith
Steve F
SF
Poon
Dehua
D
Huang
Mitchell
M
Green
Christopher
C
King
Lida
L
Tehrani
Jeffrey R
JR
Roppe
Janice
J
Chung
Deborah P
DP
Chapman
Merryl
M
Cramer
Nicholas D P
ND
Cosford
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