Structure-activity studies for a novel series of tricyclic substituted hexahydrobenz[e]isoindole alpha(1A) adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia (BPH).
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Meyer MD, Altenbach RJ, Basha FZ, Carroll WA, Condon S, Elmore SW, Kerwin JF Jr, Sippy KB, Tietje K, Wendt MD, Hancock AA, Brune ME, Buckner SA, Drizin I
Structure-activity studies for a novel series of tricyclic substituted hexahydrobenz[e]isoindole alpha(1A) adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia (BPH).
J Med Chem. 2000 Apr 20;43(8):1586-603.
- PubMed ID
- 10780916 [ View in PubMed]
- Abstract
In search of a uroselective agent that exhibits a high level of selectivity for the alpha(1A) receptor, a novel series of tricyclic hexahydrobenz[e]isoindoles was synthesized. A generic pharmacophoric model was developed requiring the presence of a basic amine core and a fused heterocyclic side chain separated by an alkyl chain. It was shown that the 6-OMe substitution with R, R stereochemistry of the ring junction of the benz[e]isoindole and a two-carbon spacer chain were optimal. In contrast to the highly specific requirements for the benz[e]isoindole portion and linker chain, a wide variety of tricyclic fused heterocyclic attachments were tolerated with retention of potency and selectivity. In vitro functional assays for the alpha(1) adrenoceptor subtypes were used to further characterize these compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Tamsulosin Alpha-1B adrenergic receptor Ki (nM) 0.2 N/A N/A Details Terazosin Alpha-1B adrenergic receptor Ki (nM) 0.69 N/A N/A Details