In vitro and in vivo evaluation of dihydropyrimidinone C-5 amides as potent and selective alpha(1A) receptor antagonists for the treatment of benign prostatic hyperplasia

alpha(1) Adrenergic receptors mediate both vascular and lower urinary tract tone, and alpha(1) receptor antagonists such as terazosin (1b) are used to treat both hypertension and benign prostatic hyperplasia (BPH). Recently, three different subtypes of this receptor have been identified, with the al pha(1A) receptor being most prevalent in lower urinary tract tissue. This p aper explores 4-aryldihydropyrimidinones attached to an aminopropyl-4-arylp iperidine via a C-5 amide as selective alpha(1A) receptor subtype antagonis ts. In receptor binding assays, these types of compounds generally display K-i values for the alpha(1a) receptor subtype <1 nM while being greater tha n 100-fold selective versus the alpha(1b) and alpha(1d) receptor subtypes. Many of these compounds were also evaluated in vivo and found to be more po tent than terazosin in both a rat model of prostate tone and a dog model of intra-urethral pressure without significantly affecting blood pressure. Wh ile many of the compounds tested displayed poor pharmacokinetics, compound 48 was found to have adequate bioavailability (>20%) and half-life (>6 h) i n both rats and dogs. Due to its selectivity for the alpha(1a) over the alp ha(1d) and alpha(1d) receptors as well as its favorable pharmacokinetic pro file, 48 has the potential to relieve the symptoms of BPH without eliciting effects on the cardiovascular system.