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 Original Research Article

Structure–activity relationship studies led to the discovery of 4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[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); α-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 (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.