2000
DOI: 10.1021/jm990567u
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Structure−Activity Studies for a Novel Series of Tricyclic Substituted Hexahydrobenz[e]isoindole α1A Adrenoceptor Antagonists as Potential Agents for the Symptomatic Treatment of Benign Prostatic Hyperplasia (BPH)

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 sp… Show more

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Cited by 46 publications
(27 citation statements)
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“…The structures of compounds 1-10 were confirmed from their IR, 1 H-NMR, 13 C-NMR and MS spectral data. Substitution of the mercapto group in 4a,d by hydrazine hydrate afforded the 2-hydrazino derivative 11 which was then cyclized by glacial acetic acid to give the triazolo derivative 12 [17,18]; the latter compound is sparingly soluble in CDCl 3 and DMSO-d 6 , precluding the use of 13 C-NMR spectroscopy as a characterization tool. Oxidation of 4a,d by iodine (Scheme 3) gave the disulfides 13a,b [19].…”
Section: Resultsmentioning
confidence: 99%
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“…The structures of compounds 1-10 were confirmed from their IR, 1 H-NMR, 13 C-NMR and MS spectral data. Substitution of the mercapto group in 4a,d by hydrazine hydrate afforded the 2-hydrazino derivative 11 which was then cyclized by glacial acetic acid to give the triazolo derivative 12 [17,18]; the latter compound is sparingly soluble in CDCl 3 and DMSO-d 6 , precluding the use of 13 C-NMR spectroscopy as a characterization tool. Oxidation of 4a,d by iodine (Scheme 3) gave the disulfides 13a,b [19].…”
Section: Resultsmentioning
confidence: 99%
“…Many thienopyrimidines are found to exhibit a variety of biological activities, including antiinflammatory [1,2], antimicrobial [3] and analgesic [4] properties, inhibition of cancer cell proliferation [5], antagonism of α 1 adrenoceptors [6] and prevention of cartilage destruction in articular diseases [7]. In continuation with our previous work on the title compounds [8,9], we report herein the synthesis of a series of novel thienopyrimidine derivatives.…”
Section: Introductionmentioning
confidence: 83%
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“…Thienopyrimidines and thienopyrimidinones are found to exhibit a variety of biological activities, including anti-inflammatory, 1 antimicrobial 2 and analgesic 3 properties, inhibition of cancer cell proliferation, 4 anti-angiogenic activities, 5 antagonism of α1-adrenoceptors, 6 and antagonism of mGluR1. 7 Consequently, thienopyrimidines have become a well-sought privileged class of compounds in drug discovery programs.…”
Section: Introductionmentioning
confidence: 99%
“…The choice of the 8-position for the insertion of side chains was made taking into account the structure-activity relationships previously seen in a series of α 1 -AR ligands designed using RN17 as template and developed at Abbott Laboratories [21]. These compounds, based on a pyrazino [2',3':4,5]thieno [3,2-d]pyrimidine-2,4(1H,3H)-dione tricyclic scaffold, bear different substituents (hydrogen, methyl, methoxy, chloro, phenyl) at the 7-and/or Figure 1) is one of them: the presence in it of a bulky substituent such as a phenyl ring at the 8-position is well tolerated whereas the shifting of the same substituent to the 7-position causes a marked drop in affinity for all three α 1 -AR subtypes [21].…”
mentioning
confidence: 99%