Discovery of DS-6930, a potent selective PPARγ modulator. Part I: Lead identification.
Bioorg Med Chem
; 26(18): 5079-5098, 2018 10 01.
Article
em En
| MEDLINE
| ID: mdl-30241907
ABSTRACT
The lead identification of a novel potent selective PPARγ agonist, DS-6930 is reported. To avoid PPARγ-related adverse effects, a partial agonist was designed to prevent the direct interaction with helix 12 of PPARγ-LBD. Because the TZD group is known to interact with helix 12, the TZD in efatutazone (CS-7017) was replaced to discover novel PPARγ intermediate partial agonist 8i. The optimization of 8i yielded 13ac with high potency in vitro. Compound 13ac exhibited robust plasma glucose lowering effects comparable to those of rosiglitazone (3â¯mg/kg) in Zucker diabetic fatty rats. Upon toxicological evaluation, compound 13ac (300â¯mg/kg) induced hemodilution to a lower extent than rosiglitazone; however, 13ac elevated liver enzyme activities. X-ray crystallography revealed no direct interaction of 13ac with helix 12, and the additional lipophilic interactions are also suggested to be related to the maximum transcriptional activity of 13ac.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
PPAR gama
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Descoberta de Drogas
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Hipoglicemiantes
Tipo de estudo:
Diagnostic_studies
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article