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.
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).
Meyer
M D
MD
Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA.
Altenbach
R J
RJ
Bai
H
H
Basha
F Z
FZ
Carroll
W A
WA
Kerwin
J F
JF
Lebold
S A
SA
Lee
E
E
Pratt
J K
JK
Sippy
K B
KB
Tietje
K
K
Wendt
M D
MD
Brune
M E
ME
Buckner
S A
SA
Hancock
A A
AA
Drizin
I
I
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D004285:Dogs; D017292:Doxazosin / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007202:Indicators and Reagents; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054833:Isoindoles; D007739:L Cells; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D011224:Prazosin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011467:Prostate / Q000378:metabolism; D011470:Prostatic Hyperplasia / Q000188:drug therapy*; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013154:Spleen / Q000378:metabolism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000378:metabolism
C429309:(3-(2-hexahydro-6-methoxy-(1H)-benz(e)isoindol-2-yl)ethyl)-6,7-dimethoxyquinazoline-4(3H)-one; C547713:ADRA1A protein, human; C547714:Adra1a protein, mouse; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D007202:Indicators and Reagents; D007211:Indoles; D054833:Isoindoles; D011799:Quinazolines; D018340:Receptors, Adrenergic, alpha-1; D011994:Recombinant Proteins; C041226:Terazosin; D017292:Doxazosin; D011224:Prazosin