4-(1,3-Dimethoxyprop-2-ylamino)-2,7-dimethyl-8-(2, 4-dichlorophenyl)pyrazolo[1,5-a]-1,3,5-triazine: a potent, orally bioavailable CRF(1) receptor antagonist.
Structure-activity studies in the pyrazolo[1,5-a]-1,3,5-triazine series led to the discovery that compound 11i (DMP696) is a potent hCRF(1) receptor antagonist (K(i) = 1.7 nM vs 7.5 nM for alpha-hel-CRF(9-41), hCRF(1) adenylate cyclase IC(50) = 82 nM vs 286 nM for alpha-hel-CRF(9-41)). Compound 11i has excellent oral pharmacokinetic profiles in rats and dogs (37% and 50% oral bioavailabilities, respectively). This compound displays good activity in the rat situational anxiety model (MED = 3 mg/kg (po)), whereas a literature standard 1 (CP154526-1) was inactive (MED > 30 mg/kg (po)). Analogue 11i reduced stereotypical mouth movements in rhesus monkeys by 50% at 21 mg/kg (po) using the human intruder paradigm. Overall, the profile of pyrazolotriazine 11i indicates that hCRF(1) receptor antagonists may be anxiolytic agents, which have reduced motor side effect profiles.
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Chemical Science Department, DuPont Pharmaceuticals Company, Experimental Station, Wilmington, Delaware 10880-0500, USA.
Gilligan
P J
PJ
Zaczek
R
R
Fitzgerald
L W
LW
McElroy
J
J
Shen
H S
HS
Saye
J A
JA
Kalin
N H
NH
Shelton
S
S
Christ
D
D
Trainor
G
G
Hartig
P
P
D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D002319:Cardiovascular System / Q000187:drug effects; D004285:Dogs; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects; D006801:Humans; D007677:Kidney Function Tests; D008253:Macaca mulatta; D008297:Male; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012143:Respiratory Physiological Phenomena / Q000187:drug effects; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000099052:CRF Receptor, Type 1
D014151:Anti-Anxiety Agents; C404928:DMP 696; D011720:Pyrazoles; D018019:Receptors, Corticotropin-Releasing Hormone; D014227:Triazines; D000099052:CRF Receptor, Type 1