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rdf:type |
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lifeskim:mentions |
umls-concept:C0070698,
umls-concept:C0205314,
umls-concept:C0220781,
umls-concept:C0243076,
umls-concept:C0679622,
umls-concept:C0870883,
umls-concept:C1292724,
umls-concept:C1524075,
umls-concept:C1707689,
umls-concept:C1883254,
umls-concept:C1883695,
umls-concept:C2003941
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pubmed:issue |
23
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pubmed:dateCreated |
1999-12-17
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pubmed:abstractText |
Dihydropyrimidinones, such as 1, represent a novel class of alpha(1a) adrenoceptor antagonists with potential for the treatment of benign prostatic hyperplasia (BPH) (see part 1 of this series). Analysis of the metabolites of 1 revealed that 4-methoxycarbonyl-4-phenylpiperidine is formed as the major metabolite and is an agonist at the mu-opioid receptor. To circumvent any potential liability resulting from the metabolite, we decided to identify alternate templates devoid of agonist activity at the mu-opioid receptor to replace the 4-methoxycarbonyl-4-phenylpiperidine moiety. The present study describes the synthesis and SAR of dihydropyrimidinones linked to substituted 4-phenylpiperazine containing side chains. Compound (+)-38 was identified as a lead compound with a binding and functional profile comparable to that of 1. The putative metabolite 2-carboxamidophenylpiperazine has negligible affinity for the mu-opioid receptor.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/ADRA1A protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Adrenergic alpha-Antagonists,
http://linkedlifedata.com/resource/pubmed/chemical/GTP-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Piperazines,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrimidinones,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Adrenergic, alpha-1,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Opioid, mu,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:ChangR SRS,
pubmed-author:ChiuGG,
pubmed-author:DiazV PVP,
pubmed-author:FangJJ,
pubmed-author:ForrayCC,
pubmed-author:GluchowskiCC,
pubmed-author:LaheSS,
pubmed-author:MarzabadiM RMR,
pubmed-author:MiaoS WSW,
pubmed-author:NagarathnamDD,
pubmed-author:O'MalleySS,
pubmed-author:RansomR WRW,
pubmed-author:SumPP,
pubmed-author:TianDD,
pubmed-author:VyasK PKP,
pubmed-author:WongW CWC,
pubmed-author:ZhangFF,
pubmed-author:ZhangKK
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pubmed:issnType |
Print
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pubmed:day |
18
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pubmed:volume |
42
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4794-803
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:10579842-Adrenergic alpha-Antagonists,
pubmed-meshheading:10579842-Animals,
pubmed-meshheading:10579842-Binding, Competitive,
pubmed-meshheading:10579842-Biological Availability,
pubmed-meshheading:10579842-Dogs,
pubmed-meshheading:10579842-Drug Design,
pubmed-meshheading:10579842-GTP-Binding Proteins,
pubmed-meshheading:10579842-Half-Life,
pubmed-meshheading:10579842-Humans,
pubmed-meshheading:10579842-Male,
pubmed-meshheading:10579842-Piperazines,
pubmed-meshheading:10579842-Prostate,
pubmed-meshheading:10579842-Pyrimidinones,
pubmed-meshheading:10579842-Rats,
pubmed-meshheading:10579842-Receptors, Adrenergic, alpha-1,
pubmed-meshheading:10579842-Receptors, Opioid, mu,
pubmed-meshheading:10579842-Recombinant Proteins,
pubmed-meshheading:10579842-Stereoisomerism,
pubmed-meshheading:10579842-Structure-Activity Relationship
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pubmed:year |
1999
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pubmed:articleTitle |
Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 3. Approaches to eliminate opioid agonist metabolites by using substituted phenylpiperazine side chains.
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pubmed:affiliation |
Departments of Chemistry and Pharmacology, Synaptic Pharmaceutical Corporation, Paramus, NJ 07652, USA.
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pubmed:publicationType |
Journal Article,
In Vitro
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