Synthesis, structure-activity relationships, and biological profiles of a quinazolinone class of histamine H3 receptor inverse agonists

A new series of quinazolinone derivatives was synthesized and evaluated as nonimidazole H(3) receptor inverse agonists. 2-Methyl-3-(4-{[3-(1-pyrrolidinyl)propy]oxy}phenyl)-5-(trifluoromethyl)-4(3H)-quinazolinone (1) was identified as a promising derivative for further evaluation following optimization of key parameters. Compound 1 has potent H3 inverse agonist activity and excellent selectivity over other histamine receptor subtypes and a panel of 115 unrelated diverse binding sites. Compound 1 also shows satisfactory pharmacokinetic profiles and brain penetrability in laboratory animals. Two hours after oral administration of 30 mg/kg of 1 to SD rats, significant elevation of brain histamine levels was observed where the brain H3 receptor was highly occupied (>90%). On the basis of species differences in P-glycoprotein (P-gp) susceptibility of I between human and rodent P-gps, the observed rodent brain permeability of I is significantly limited by P-gp mediated efflux in rodents, whereas the extent of P-gp mediated efflux in humans should be very small or negligible. The potential of 1 to be an efficacious drug was demonstrated by its excellent brain penetrability and receptor occupancy in P-gp-deficient CF-1 mice.