Document Detail

Synthesis of 2-{2-[(α/β-naphthalen-1-ylsulfonyl)amino]-1,3-thiazol-4-yl} acetamides with 11β-hydroxysteroid dehydrogenase inhibition and in combo antidiabetic activities.
MedLine Citation:
PMID:  24462849     Owner:  NLM     Status:  Publisher    
Compounds 1-10 were designed using a bioisosteric approach and were prepared using a short synthetic route. The in vitro inhibitory activity of the compounds against 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) was evaluated. Compounds 5 (α-series) and 10 (β-series) had a moderate inhibitory enzyme activity (55.26% and 67.03% inhibition at 10 μM, respectively) and were as active as BVT.14225 (positive control). Both compounds have a piperidine ring in their structure, but the most active (10) was selected to establish its in vivo antidiabetic effect using a non insulin-dependent diabetes mellitus rat model. The antidiabetic activity of compound 10 was determined at 50 mg/kg single dose in an acute model, and also by short term sub-chronic administration for 5 days. The results indicated a significant decrease of plasma glucose levels, similar than BVT.14225. Additionally, a molecular docking of the most active compounds of each series into the ligand binding pocket of one subunit of human 11β-HSD1 was performed. In this model the oxygen atom of the sulfonamide make hydrogen bond interactions with the catalytic residues Ser170 and Ala172. We also observed important π-π interactions between the naphthyl group and Tyr177.
Gabriel Navarrete-Vázquez; Maria Guadalupe Morales-Vilchis; Samuel Estrada-Soto; Juan José Ramírez-Espinosa; Sergio Hidalgo-Figueroa; Carlos Nava-Zuazo; Hugo Tlahuext; Ismael Leon-Rivera; José L Medina-Franco; Fabian López-Vallejo; Scott P Webster; Margaret Binnie; Rolffy Ortiz-Andrade; Hermenegilda Moreno-Diaz
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-1-8
Journal Detail:
Title:  European journal of medicinal chemistry     Volume:  74C     ISSN:  1768-3254     ISO Abbreviation:  Eur J Med Chem     Publication Date:  2014 Jan 
Date Detail:
Created Date:  2014-1-27     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0420510     Medline TA:  Eur J Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  179-186     Citation Subset:  -    
Copyright Information:
Copyright © 2014 Elsevier Masson SAS. All rights reserved.
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