Design and Synthesis of Novel α1a Adrenoceptor-Selective Antagonists. 1. Structure−Activity Relationship in Dihydropyrimidinones
- 27 October 1999
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 42 (23) , 4764-4777
- https://doi.org/10.1021/jm990200p
Abstract
Dihydropyrimidinones such as compound 12 exhibited high binding affinity and subtype selectivity for the cloned human α1a receptor. Systematic modifications of 12 led to identification of highly potent and subtype-selective compounds such as (+)-30 and (+)-103, with high binding affinity (Ki = 0.2 nM) for α1a receptor and greater than 1500-fold selectivity over α1b and α1d adrenoceptors. The compounds were found to be functional antagonists in human, rat, and dog prostate tissues. Compound (+)-103 exhibited excellent selectively to inhibit intraurethral pressure (IUP) as compared to lowering diastolic blood pressure (DBP) in mongrel dogs (Kb(DBP)/Kb(IUP) = 40) suggesting uroselectivity for α1a-selective compounds.Keywords
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