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 CRF1 Receptor Antagonist

• Published in: Journal of medicinal chemistry 2000-02, Vol.43 (3), p.449-456
• Main Authors: He, Liqi, Gilligan, Paul J, Zaczek, Robert, Fitzgerald, Lawrence W, McElroy, John, Shen, H-S. L, Saye, Jo Anne, Kalin, Ned H, Shelton, Steven, Christ, David, Trainor, George, Hartig, Paul
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9904351

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 hCRF1 receptor antagonist (K i = 1.7 nM vs 7.5 nM for α-hel-CRF(9−41), hCRF1 adenylate cyclase IC50 = 82 nM vs 286 nM for α-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 hCRF1 receptor antagonists may be anxiolytic agents, which have reduced motor side effect profiles.