title: The discovery of 4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1 ,5-a]-pyrimidine: a corticotropin-releasing factor (hCRF1) antagonist.
abstract: Structure activity relationship studies led to the discovery of 4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazo lo-[1,5-a]-pyrimidine 11-31 (DMP904), whose pharmacological profile strongly supports the hypothesis that hCRF1 antagonists may be potent anxiolytic drugs. Compound 11-31 (hCRF1 Ki = 1.0+/-0.2 nM (n = 8)) was a potent antagonist of hCRF1-coupled adenylate cyclase activity in HEK293 cells (IC50= 10.0+/-0.01 nM versus 10 nM r/hCRF, n = 8); alpha-helical CRF(9-41) had weaker potency (IC50 = 286+/-63 nM, n = 3). Analogue 11-31 had good oral activity in the rat situational anxiety test; the minimum effective dose for 11-31 was 0.3 mg/kg (po). Maximal efficacy (approximately 57% reduction in latency time in the dark compartment) was observed at this dose. Chlordiazepoxide caused a 72% reduction in latency at 20 mg/kg (po). The literature compound 1 (CP154526-1, 30 mg/kg (po)) was inactive in this test. Compound 11-31 did not inhibit open-field locomotor activity at 10, 30, and 100 mg/kg (po) in rats. In beagle dogs, this compound (5 mg/kg, iv, po) afforded good plasma levels. The key iv pharmacokinetic parameters were t1/2, CL and Vd,ss values equal to 46.4+/-7.6 h. 0.49+/-0.08 L/kg/h and 23.0+/-4.2 L/kg, respectively. After oral dosing, the mean Cmax, Tmax t1/2 and bioavailability values were equal to 1260+/-290 nM, 0.75+/-0.25 h. 45.1+/-10.2 h and 33.1%, respectively. The overall rat behavioral profile of this compound suggests that it may be an anxiolytic drug with a low motor side effect liability.
authors.affiliation: DuPont Pharmaceuticals Co., Chemical and Physical Sciences Departent, Experimental Station, Wilmington, DE 10880-0500, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Gilligan
authors.forename: C
authors.initials: C
authors.lastname: Baldauf
authors.forename: A
authors.initials: A
authors.lastname: Cocuzza
authors.forename: D
authors.initials: D
authors.lastname: Chidester
authors.forename: R
authors.initials: R
authors.lastname: Zaczek
authors.forename: L W
authors.initials: LW
authors.lastname: Fitzgerald
authors.forename: J
authors.initials: J
authors.lastname: McElroy
authors.forename: M A
authors.initials: MA
authors.lastname: Smith
authors.forename: H S
authors.initials: HS
authors.lastname: Shen
authors.forename: J A
authors.initials: JA
authors.lastname: Saye
authors.forename: D
authors.initials: D
authors.lastname: Christ
authors.forename: G
authors.initials: G
authors.lastname: Trainor
authors.forename: D W
authors.initials: DW
authors.lastname: Robertson
authors.forename: P
authors.initials: P
authors.lastname: Hartig
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D023421:Models, Animal; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats
chemical_list: C417190:4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)pyrazolo(1,5-a)pyrimidine; D014151:Anti-Anxiety Agents; D011720:Pyrazoles; D011743:Pyrimidines; D003346:Corticotropin-Releasing Hormone