In Vitro and in Vivo Evaluation of Dihydropyrimidinone C-5 Amides as Potent and Selective α1A Receptor Antagonists for the Treatment of Benign Prostatic Hyperplasia

• Published in: Journal of medicinal chemistry 2000-07, Vol.43 (14), p.2703-2718
• Main Authors: Barrow, James C, Nantermet, Philippe G, Selnick, Harold G, Glass, Kristen L, Rittle, Kenneth E, Gilbert, Kevin F, Steele, Thomas G, Homnick, Carl F, Freidinger, Roger M, Ransom, Rick W, Kling, Paul, Reiss, Duane, Broten, Theodore P, Schorn, Terry W, Chang, Raymond S. L, O'Malley, Stacey S, Olah, Timothy V, Ellis, Joan D, Barrish, Andrea, Kassahun, Kelem, Leppert, Paula, Nagarathnam, Dhanapalan, Forray, Carlos
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Medical sciences; Pharmacology. Drug treatments; Urinary system
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm990612y

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 α1A 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 α1A receptor subtype antagonists. In receptor binding assays, these types of compounds generally display K i values for the α1a receptor subtype 20%) and half-life (>6 h) in both rats and dogs. Due to its selectivity for the α1a over the α1b and α1d 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.