Identification, optimisation and in vivo evaluation of oxadiazole DGAT-1 inhibitors for the treatment of obesity and diabetes

Autor:	Graeme C. Moody, Alleyn T. Plowright, J. Matthew Wood, Matthew S. Addie, Scott Boyd, Paul D. Kemmitt, David Whalley, Chris Sheldon, Andrew V. Turnbull, Stephen Chapman, Andrew G. Leach, Pablo Morentin Gutierrez, Paul Schofield, Linda K. Buckett, William McCoull, Nicholas John Newcombe, Alan Martin Birch, Chloe Jenner, Martin J. Packer, Thorsten Nowak, Robert D. M. Davies, Susan Birtles, Steven Wang, Steve Stokes, Roger John Butlin, Suzanne S. Bowker, John Revill, Craig S. Donald, Clive Green
Rok vydání:	2012
Předmět:	Quantitative structure–activity relationship High-throughput screening Carboxylic acid Clinical Biochemistry Drug Evaluation Preclinical Pharmaceutical Science Oxadiazole Quantitative Structure-Activity Relationship Ligands Biochemistry chemistry.chemical_compound Mice Dogs In vivo Drug Discovery Diabetes Mellitus Potency Animals Humans Hypoglycemic Agents Diacylglycerol O-Acyltransferase Obesity Enzyme Inhibitors Molecular Biology PK/PD models chemistry.chemical_classification Oxadiazoles Chemistry Organic Chemistry Combinatorial chemistry High-Throughput Screening Assays Rats Lipophilic efficiency Drug Design Molecular Medicine Half-Life
Zdroj:	Bioorganicmedicinal chemistry letters. 22(12)
ISSN:	1464-3405
Popis:	A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2e16429eb9afcdf02cbee31792660806 https://pubmed.ncbi.nlm.nih.gov/22608962 Zobrazit plný text záznamu Full Text from ScienceDirect