Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 1. Structure-activity relationship in dihydropyrimidinones.
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Nagarathnam D, Miao SW, Lagu B, Chiu G, Fang J, Murali Dhar TG, Zhang J, Tyagarajan S, Marzabadi MR, Zhang F, Wong WC, Sun W, Tian D, Wetzel JM, Forray C, Chang RS, Broten TP, Ransom RW, Schorn TW, Chen TB, O'Malley S, Kling P, Schneck K, Bendesky R, Harrell CM, et al.
Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 1. Structure-activity relationship in dihydropyrimidinones.
J Med Chem. 1999 Nov 18;42(23):4764-77.
- PubMed ID
- 10579840 [ View in PubMed]
- Abstract
Dihydropyrimidinones such as compound 12 exhibited high binding affinity and subtype selectivity for the cloned human alpha(1a) receptor. Systematic modifications of 12 led to identification of highly potent and subtype-selective compounds such as (+)-30 and (+)-103, with high binding affinity (K(i) = 0.2 nM) for alpha(1a) receptor and greater than 1500-fold selectivity over alpha(1b) and alpha(1d) 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 (K(b)(DBP)/K(b)(IUP) = 40) suggesting uroselectivity for alpha(1a)-selective compounds.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Terazosin Alpha-1A adrenergic receptor Ki (nM) 6.9 N/A N/A Details Terazosin Alpha-1A adrenergic receptor Ki (nM) 4 N/A N/A Details Terazosin Alpha-1B adrenergic receptor Ki (nM) 1.9 N/A N/A Details Terazosin Alpha-1D adrenergic receptor Ki (nM) 3.5 N/A N/A Details