Discovery and optimization of efficacious neutral 4-amino-6-biphenyl-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5-one diacylglycerol acyl transferase-1 (DGAT1) inhibitors

Autor:	Frederick W. Goldberg, Alan Martin Birch, Andrew G. Leach, Wendy L. Snelson, Linda K. Buckett, Sam D. Groombridge, Pablo Morentin Gutierrez, Susan Birtles, Clare D. Hammond
Rok vydání:	2013
Předmět:	Pharmacology Biphenyl Stereochemistry Organic Chemistry Pharmaceutical Science Biochemistry Acyl transferase Polar surface area chemistry.chemical_compound chemistry Pharmacokinetics Lipophilic efficiency Drug Discovery Molecular Medicine Potency Diacylglycerol kinase
Zdroj:	MedChemComm. 4:165-174
ISSN:	2040-2511 2040-2503
DOI:	10.1039/c2md20231j
Popis:	A series of neutral DGAT1 inhibitors with good potency and pharmacokinetics (PK) has been designed by modification of an acidic startpoint. This was achieved by selecting the acid with the highest ligand lipophilicity efficiency (LLE) and replacing the acid with neutral isosteres. PK properties (Fabs) were then improved by removing the sidechain to reduce molecular weight and polar surface area (PSA). Compound 13 has shown good cross-species PK, with pre-clinical efficacy and PK/PD relationships comparable to those previously described for acidic inhibitors.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::1b7b268fa1152bf9f3e80d035f31f2d5 https://doi.org/10.1039/c2md20231j Zobrazit plný text záznamu