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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
24
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pubmed:dateCreated |
2006-11-27
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pubmed:abstractText |
The high expression of MCH in the hypothalamus with the lean hypophagic phenotype coupled with increased resting metabolic rate and resistance to high fat diet-induced obesity of MCH KO mice has spurred considerable efforts to develop small molecule MCHR1 antagonists. Starting from a lead thienopyrimidinone series, structure-activity studies at the 3- and 6-positions of the thienopyrimidinone core afforded potent and selective MCHR1 antagonists with representative examples having suitable pharmacokinetic properties. Based on structure-activity relationships, a structural model for MCHR1 was constructed to explain the binding mode of these antagonists. In general, a good correlation was observed between pKas and activity in the right-hand side of the template, with Asp123 playing an important role in the enhancement of binding affinity. A representative example when evaluated chronically in diet-induced obese mice resulted in good weight loss effects. These antagonists provide a viable lead series in the discovery of new therapies for the treatment of obesity.
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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 |
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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:Al-BarazanjiKamal AKA,
pubmed-author:BighamEric CEC,
pubmed-author:BishopMichael JMJ,
pubmed-author:BrittChristy SCS,
pubmed-author:CarltonDavid LDL,
pubmed-author:FeldmanPaul LPL,
pubmed-author:GoetzAaron SAS,
pubmed-author:GrizzleMary KMK,
pubmed-author:GuoYu CYC,
pubmed-author:HandlonAnthony LAL,
pubmed-author:HertzogDonald LDL,
pubmed-author:IgnarDiane MDM,
pubmed-author:LangDaniel GDG,
pubmed-author:OttRonda JRJ,
pubmed-author:PeatAndrew JAJ,
pubmed-author:TavaresFrancis XFX,
pubmed-author:ZhouHui-QiangHQ
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pubmed:issnType |
Print
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pubmed:day |
30
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pubmed:volume |
49
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
7095-107
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pubmed:dateRevised |
2008-10-28
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pubmed:meshHeading |
pubmed-meshheading:17125262-Administration, Oral,
pubmed-meshheading:17125262-Animals,
pubmed-meshheading:17125262-Anti-Obesity Agents,
pubmed-meshheading:17125262-Biological Availability,
pubmed-meshheading:17125262-CHO Cells,
pubmed-meshheading:17125262-Cricetinae,
pubmed-meshheading:17125262-Cricetulus,
pubmed-meshheading:17125262-Ether-A-Go-Go Potassium Channels,
pubmed-meshheading:17125262-Genes, Reporter,
pubmed-meshheading:17125262-Half-Life,
pubmed-meshheading:17125262-Humans,
pubmed-meshheading:17125262-Mice,
pubmed-meshheading:17125262-Mice, Obese,
pubmed-meshheading:17125262-Models, Molecular,
pubmed-meshheading:17125262-Pyrimidines,
pubmed-meshheading:17125262-Rats,
pubmed-meshheading:17125262-Receptors, Somatostatin,
pubmed-meshheading:17125262-Structure-Activity Relationship,
pubmed-meshheading:17125262-Thiophenes
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pubmed:year |
2006
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pubmed:articleTitle |
Potent, selective, and orally efficacious antagonists of melanin-concentrating hormone receptor 1.
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pubmed:affiliation |
Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA. fxt66911@gsk.com
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pubmed:publicationType |
Journal Article
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