Document Detail

Relating molecular properties and in vitro assay results to in vivo drug disposition and toxicity outcomes.
MedLine Citation:
PMID:  22716080     Owner:  NLM     Status:  Publisher    
A primary goal of lead optimization is to identify compounds with improved absorption, distribution, metabolism, excretion and toxicity (ADMET) properties. A number of reports have linked computed molecular properties to desirable in vivo ADMET outcomes, but a significant limitation of these analyses is the failure to control statistically for possible covariates. We examine the relationship between molecular properties and in vitro surrogate assays vs. in vivo properties within 173 chemical series from a database of 3773 compounds with rodent pharmacokinetic and toxicology data. This approach identifies the following pairs of surrogates as most predictive among those examined: rat primary hepatocyte (RPH) cytolethality / volume of distribution (Vd) for in vivo toxicology outcomes, scaled microsome metabolism / calculated logP for in vivo unbound clearance, and calculated logD / kinetic aqueous solubility for thermodynamic solubility. The impact of common functional group substitutions is examined, and provides insights for compound design.
Jeffrey Sutherland; John Wallace Raymond; James Leonard Stevens; Thomas Baker; David Watson
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-6-20
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  -     ISSN:  1520-4804     ISO Abbreviation:  -     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-6-21     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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