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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
12
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pubmed:dateCreated |
2011-6-16
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pubmed:databankReference |
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pubmed:abstractText |
Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-? (PPAR?) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2a bound to the ligand binding domain of human PPAR? confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPAR? activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridine (2l) was identified as a potent angiotensin II type I receptor blocker (IC(50) = 1.6 nM) with partial PPAR? agonism (EC(50) = 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2l was demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2l was highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat.
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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 |
Jun
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pubmed:issn |
1520-4804
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pubmed:author |
pubmed-author:BiggeChristopher FCF,
pubmed-author:Casimiro-GarciaAgustinA,
pubmed-author:ChenJingJ,
pubmed-author:DavisJo AnnJA,
pubmed-author:DudleyDanette ADA,
pubmed-author:EdmundsJeremy JJJ,
pubmed-author:EllisTeresaT,
pubmed-author:EsmaeilNadiaN,
pubmed-author:FilzenGary FGF,
pubmed-author:FlynnDeclanD,
pubmed-author:GeyerAndrewA,
pubmed-author:HeemstraRonald JRJ,
pubmed-author:JalaieMehranM,
pubmed-author:OhrenJeffrey FJF,
pubmed-author:OstroskiRobertR,
pubmed-author:SchaumRobert PRP,
pubmed-author:StonerChadC
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pubmed:issnType |
Electronic
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pubmed:day |
23
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pubmed:volume |
54
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4219-33
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pubmed:meshHeading |
pubmed-meshheading:21557540-Administration, Oral,
pubmed-meshheading:21557540-Angiotensin II Type 1 Receptor Blockers,
pubmed-meshheading:21557540-Animals,
pubmed-meshheading:21557540-Antihypertensive Agents,
pubmed-meshheading:21557540-Biological Availability,
pubmed-meshheading:21557540-Blood Glucose,
pubmed-meshheading:21557540-Crystallography, X-Ray,
pubmed-meshheading:21557540-Drug Partial Agonism,
pubmed-meshheading:21557540-Humans,
pubmed-meshheading:21557540-Hypoglycemic Agents,
pubmed-meshheading:21557540-Imidazoles,
pubmed-meshheading:21557540-Insulin Resistance,
pubmed-meshheading:21557540-Male,
pubmed-meshheading:21557540-Models, Molecular,
pubmed-meshheading:21557540-PPAR gamma,
pubmed-meshheading:21557540-Pyridines,
pubmed-meshheading:21557540-Radioligand Assay,
pubmed-meshheading:21557540-Rats,
pubmed-meshheading:21557540-Rats, Inbred SHR,
pubmed-meshheading:21557540-Stereoisomerism,
pubmed-meshheading:21557540-Structure-Activity Relationship,
pubmed-meshheading:21557540-Transcriptional Activation,
pubmed-meshheading:21557540-Triglycerides
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pubmed:year |
2011
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pubmed:articleTitle |
Discovery of a series of imidazo[4,5-b]pyridines with dual activity at angiotensin II type 1 receptor and peroxisome proliferator-activated receptor-?.
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pubmed:affiliation |
Pfizer Global Research and Development, Groton Laboratories, Eastern Point Rd, Groton, Connecticut 06340, United States. agustin.casimiro-garcia@pfizer.com
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, Non-P.H.S.,
Research Support, Non-U.S. Gov't
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