Design and synthesis of novel alpha1a adrenoceptor-selective dihydropyridine antagonists for the treatment of benign prostatic hyperplasia.

D Nagarathnam, J M Wetzel, S W Miao, M R Marzabadi, G Chiu, W C Wong, X Hong, J Fang, C Forray, T A Branchek, W E Heydorn, R S Chang, T Broten, T W Schorn, C Gluchowski

Departments of Chemistry, Pharmacology, and Pharmaceutical Operations, Synaptic Pharmaceutical Corporation, Paramus, New Jersey 07652, USA.

Journal of medicinal chemistry 1998 Dec 17

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We report the synthesis and evaluation of novel alpha1a adrenoceptor subtype-selective antagonists. Systematic modification of the lipophilic 4,4-diphenylpiperidinyl moiety of the dihydropyridine derivatives 1 and 2 provided several highly selective and potent alpha1a antagonists. From this series, we identified the 4-(methoxycarbonyl)-4-phenylpiperidine analogue SNAP 5540 (-) [(-)-63] for further characterization. When examined in an isolated human prostate tissue assay, this compound was found to have a Ki of 2.8 nM, in agreement with the cloned human receptor binding data (Ki = 2.42 nM). Further evaluation of the compound in isolated dog prostate tissue showed a Ki of 3.6 nM and confirmed it to be a potent antagonist (Kb = 1.6 nM). In vivo, this compound effectively blocked the phenylephrine-stimulated increase in intraurethral pressure (IUP) in mongrel dogs, at doses which did not significantly affect the arterial pressure (diastolic blood pressure, DBP), with a DBP Kb/IUP Kb ratio of 16. In addition, (-)-63 also showed greater than 40 000-fold selectivity over the rat L-type calcium channel and 200-fold selectivity over several G protein-coupled receptors, including histamine and serotonin subtypes. These findings prove that alpha1a adrenoceptor-subtype selective antagonists such as (-)-63 may be developed as uroselective agents for an improved treatment of BPH over nonselective alpha1 antagonists such as prazosin and terazosin, with fewer side effects.

Citation

D Nagarathnam, J M Wetzel, S W Miao, M R Marzabadi, G Chiu, W C Wong, X Hong, J Fang, C Forray, T A Branchek, W E Heydorn, R S Chang, T Broten, T W Schorn, C Gluchowski. Design and synthesis of novel alpha1a adrenoceptor-selective dihydropyridine antagonists for the treatment of benign prostatic hyperplasia. Journal of medicinal chemistry. 1998 Dec 17;41(26):5320-33