Doxazosin, a case history.
Demonstration that the antihypertensive activity of prazosin resulted from blockade of postjunctional alpha 1-adrenoceptors stimulated interest in identifying the structural basis for this novel pharmacological profile. SARs suggested that 2,4-diamino-6,7-dimethoxyquinazoline was the pharmacophore for alpha 1-adrenoceptor recognition and that receptor occupancy was similar to noradrenaline. This model stressed the importance of charge-reinforced hydrogen bonding rather than particular roles played by individual nitrogen atoms. Modification of the quinazoline 2-substituent influenced alpha 1-adrenoceptor affinity and antihypertensive activity, particularly duration of action. These studies led to a novel series of quinazoline-benzodioxanoyl derivatives from which doxazosin was selected for detailed evaluation. Doxazosin is a potent, selective alpha 1-adrenoceptor antagonist which produces long-lasting antihypertensive effects in laboratory animals, with little effect on heart rate. In man, the plasma half-life of doxazosin is approximately 10 hr., consistent with clinical evidence that once-daily administration provides 24 hr. blood pressure control.
Campbell
S F
SF
Pfizer Central Research, Sandwich, Kent.
Davey
M J
MJ
D000818:Animals; D017292:Doxazosin; D006801:Humans; D011224:Prazosin / Q000031:analogs & derivatives* / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
D014665:Vasodilator Agents; D017292:Doxazosin; D011224:Prazosin