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

James C. Barrow, Philippe G. Nantermet, Harold G. Selnick, Kristen L. Glass, Kenneth E. Rittle, Kevin F. Gilbert, Thomas G. Steele, Carl F. Homnick, Roger M. Freidinger, Rick W. Ransom, Paul Kling, Duane Reiss, Theodore P. Broten, Terry W. Schorn, Raymond S.L. Chang, Stacey S. O'Malley, Timothy V. Olah, Joan D. Ellis, Andrea Barrish, Kelem KassahunPaula Leppert, Dhanapalan Nagarathnam, Carlos Forray

Research output: Contribution to journalArticle

Abstract

α1 Adrenergic receptors mediate both vascular and lower urinary tract tone, and α1 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 α(1A) receptor being most prevalent in lower urinary tract tissue. This paper explores 4-aryldihydropyrimidinones attached to an aminopropyl-4- arylpiperidine via a C-5 amide as selective α(1A) receptor subtype antagonists. In receptor binding assays, these types of compounds generally display K(i) values for the α(1a) receptor subtype <1 nM while being greater than 100-fold selective versus the α(1b) and α(1d) receptor subtypes. Many of these compounds were also evaluated in vivo and found to be more potent than terazosin in both a rat model of prostate tone and a dog model of intra-urethral pressure without significantly affecting blood pressure. While many of the compounds tested displayed poor pharmacokinetics, compound 48 was found to have adequate bioavailability (>20%) and half-life (>6 h) in both rats and dogs. Due to its selectivity for the α(1a) over the α(1b) and α(1d) receptors as well as its favorable pharmacokinetic profile, 48 has the potential to relieve the symptoms of BPH without eliciting effects on the cardiovascular system.

Original languageEnglish (US)
Pages (from-to)2703-2718
Number of pages16
JournalJournal of medicinal chemistry
Volume43
Issue number14
DOIs
StatePublished - Jul 13 2000
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Barrow, J. C., Nantermet, P. G., Selnick, H. G., Glass, K. L., Rittle, K. E., Gilbert, K. F., Steele, T. G., Homnick, C. F., Freidinger, R. M., Ransom, R. W., Kling, P., Reiss, D., Broten, T. P., Schorn, T. W., Chang, R. S. L., O'Malley, S. S., Olah, T. V., Ellis, J. D., Barrish, A., ... Forray, C. (2000). In vitro, and in vivo, evaluation of dihydropyrimidinone C-5 amides as potent and selective α(1A) receptor antagonists for the treatment of benign prostatic hyperplasia. Journal of medicinal chemistry, 43(14), 2703-2718. https://doi.org/10.1021/jm990612y