Document Detail

Free-Wilson and Structural Approaches to Co-optimising Human and Rodent Isoform Potency for 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors.
MedLine Citation:
PMID:  23153367     Owner:  NLM     Status:  Publisher    
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) has been a target of intensive research effort across the pharmaceutical industry, due to its potential for the treatment of type II diabetes and other elements of the metabolic syndrome. In order to demonstrate the value of 11β-HSD1 in pre-clinical models we required inhibitors with good potency against both human and rodent isoforms. Herein we describe our efforts to understand how to co-optimize human and murine potency within the (5-hydroxy-2-adamantyl)-pyrimidine-5-carboxamide series. Two approaches are described - a data driven (Free-Wilson) analysis and a structure-based design approach. The conclusions from these approaches were used to inform an efficient campaign to design compounds with consistently good human/murine potency within a logD7.4 range of 1-3. Compounds 20 and 26 demonstrated good rodent PK, which allowed us to demonstrate a PK/PD relationship in rat and mouse. We then evaluated 26 against glycaemic and bodyweight endpoints in murine disease models, where it demonstrated glucose and bodyweight efficacy at 300 mg/kg/day but only bodyweight efficacy at 50 mg/kg/day, despite providing >90% target engagement in the liver.
Frederick Woolf Goldberg; Andrew George Leach; James S Scott; Wendy Snelson; Sam Groombridge; Craig Donald; Stuart Bennett; Cristian Bodin; Pablo Morentin Gutierrez; Amy Gyte
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-11-16
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  -     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-16     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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