Design and synthesis of novel alpha(1a) adrenoceptor-selective dihydropyridine antagonists for the treatment of benign prostatic hyperplasia

• Published in: Journal of medicinal chemistry Vol. 41; no. 26; pp. 5320 - 5333
• Main Authors: Nagarathnam, D, Wetzel, JM, Miao, SW, Marzabadi, MR, Chiu, G, Wong, WC, Hong, XF, Fang, J, Forray, C, Branchek, TA, Heydorn, WE, Chang, RSL, Broten, T, Schorn, TW, Gluchowski, C
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 17.12.1998
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; HYPERTROPHY; SMOOTH-MUSCLE; ALPHA-ADRENOCEPTOR; EFFICACY; SAFETY; CHANNEL ANTAGONIST; RECEPTOR; BINDING
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980506g

We report the synthesis and evaluation of novel alpha(1a) 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 alpha(1a), 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 K-i of 2.8 nM, in agreement with the cloned human receptor binding data (K-i = 2.42 nM). Further evaluation of the compound in isolated dog prostate tissue showed a K-i of 3.6 nM and confirmed it to be a potent antagonist (K-b = 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 K-b/IUP K-b 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 alpha(1a) adrenoceptor-subtype selective antagonists such as (-)-63 may be developed as uroselective agents for an improved treatment of BPH over nonselective alpha(1) antagonists such as prazosin and terazosin, with fewer side effects.