Structure-activity studies for a novel series of bicyclic substituted hexahydrobenz[e]isoindole alpha1A adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia

M D Meyer; R J Altenbach; H Bai; F Z Basha; W A Carroll; J F Kerwin Jr; S A Lebold; E Lee; J K Pratt; K B Sippy; K Tietje; M D Wendt; M E Brune; S A Buckner; A A Hancock; I Drizin

doi:10.1021/jm000541z

Structure-activity studies for a novel series of bicyclic substituted hexahydrobenz[e]isoindole alpha1A adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia

J Med Chem. 2001 Jun 7;44(12):1971-85. doi: 10.1021/jm000541z.

Authors

M D Meyer¹, R J Altenbach, H Bai, F Z Basha, W A Carroll, J F Kerwin Jr, S A Lebold, E Lee, J K Pratt, K B Sippy, K Tietje, M D Wendt, M E Brune, S A Buckner, A A Hancock, I Drizin

Affiliation

¹ Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA.

PMID: 11384242
DOI: 10.1021/jm000541z

Abstract

In search of a uroselective alpha1A subtype selective antagonist, a novel series of 6-OMe hexahydrobenz[e]isoindoles attached to a bicyclic heterocyclic moiety via a two-carbon linker was synthesized. It was found that in contrast to the previously described series of tricyclic heterocycles,(1) this bicyclic series has very specific requirements for the heterocyclic attachments. The most important structural features contributing to the alpha1A/alpha1B selectivity of these compounds were identified. In vitro functional assays for the alpha1 adrenoceptor subtypes were used to further characterize the most selective compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity. Compound 48 showed the highest degree of selectivity in the radioligand binding assays (56-fold), in the in vitro functional tests (80-fold), and for in vivo prostate selectivity (960-fold).

MeSH terms

Adrenergic alpha-1 Receptor Antagonists*
Adrenergic alpha-Antagonists / chemical synthesis*
Adrenergic alpha-Antagonists / chemistry
Adrenergic alpha-Antagonists / pharmacology
Animals
Cell Line
Dogs
Doxazosin / pharmacology
Drug Design
Humans
Indicators and Reagents
Indoles / chemical synthesis*
Indoles / chemistry
Indoles / pharmacology
Isoindoles
L Cells
Male
Mice
Models, Molecular
Molecular Conformation
Prazosin / analogs & derivatives*
Prazosin / pharmacology
Prostate / metabolism
Prostatic Hyperplasia / drug therapy*
Quinazolines / chemical synthesis*
Quinazolines / chemistry
Quinazolines / pharmacology
Radioligand Assay
Rats
Receptors, Adrenergic, alpha-1
Recombinant Proteins / antagonists & inhibitors
Spleen / metabolism
Structure-Activity Relationship
Vas Deferens / metabolism

Substances

(3-(2-hexahydro-6-methoxy-(1H)-benz(e)isoindol-2-yl)ethyl)-6,7-dimethoxyquinazoline-4(3H)-one
ADRA1A protein, human
Adra1a protein, mouse
Adrenergic alpha-1 Receptor Antagonists
Adrenergic alpha-Antagonists
Indicators and Reagents
Indoles
Isoindoles
Quinazolines
Receptors, Adrenergic, alpha-1
Recombinant Proteins
Terazosin
Doxazosin
Prazosin