ABSTRACT
A group of small molecule thienopyrimidine inhibitors of Notum Pectinacetylesterase are described. We explored both 2-((5,6-thieno[2,3-d]pyrimidin-4-yl)thio)acetic acids and 2-((6,7-thieno[3,2-d]pyrimidin-4-yl)thio)acetic acids. In both series, highly potent, orally active Notum Pectinacetylesterase inhibitors were identified.
Subject(s)
Enzyme Inhibitors/pharmacology , Esterases/antagonists & inhibitors , Femur/drug effects , Osteogenesis/drug effects , Pyrimidines/pharmacology , Animals , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Esterases/metabolism , Femur/anatomy & histology , Femur/growth & development , Humans , Mice , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity RelationshipABSTRACT
The synthesis, SAR, and in vivo activity of inhibitors of delta-5 desaturase are described. Ring-constraint of the initial series provided access to a variety of in vitro active chemotypes, from which the indazole was selected. Examples from the indazole series displayed in vivo activity in reducing the enzymatic activity of liver delta-5 desaturase.
Subject(s)
Amides/pharmacology , Drug Design , Enzyme Inhibitors/pharmacology , Fatty Acid Desaturases/antagonists & inhibitors , Metabolic Syndrome/drug therapy , Amides/chemical synthesis , Amides/chemistry , Animals , Delta-5 Fatty Acid Desaturase , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Fatty Acid Desaturases/metabolism , Humans , Liver/enzymology , Metabolic Syndrome/enzymology , Metabolic Syndrome/metabolism , Mice , Molecular Structure , Structure-Activity RelationshipABSTRACT
A series of novel aryloxazolidine-2,4-diones was synthesized. A structure-activity relationship study of these compounds led to the identification of potent, orally active PPAR dual alpha/gamma agonists. Based on the results of efficacy studies in the db/db mice model of type 2 diabetes and the desired pharmacokinetic parameters, compound 12 was selected for further profiling.
