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
A group of small molecule thienochromenes inhibitors of Notum Pectinacetylesterase are described. We developed SAR on three series based on carbon, oxygen and sulfur replacement of the 5-position. In each series, highly potent Notum Pectinacetylesterase inhibitors were identified.
Subject(s)
Benzopyrans/chemistry , Enzyme Inhibitors/chemistry , Esterases/antagonists & inhibitors , Animals , Benzopyrans/pharmacokinetics , Benzopyrans/therapeutic use , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , Esterases/metabolism , Femur/physiology , Half-Life , Humans , Inhibitory Concentration 50 , Male , Mice , Osteoporosis/drug therapy , Osteoporosis/physiopathology , Protein Binding , 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
The conformation-activity relationships for the biologically active polyketide, epothilone, have been determined. Computer-based molecular modeling and high field NMR techniques have provided the solution preferences for epothilones and. For the C1-C8 polypropionate region, two conformational families, conformers 1 and 2, have been identified as having significant populations in polar and non-polar solvents. In the C11-C15 region, additional flexibility was observed and two local conformations have been identified as important, conformers 3 and 4. Epothilone analogues with altered conformational profiles have been designed and synthesized. Conformational analysis and the results of biological assays have been correlated to provide increased understanding of the biologically active conformation for the epothilone class of natural product. Conformation-activity relationships have been shown to be an important complement to structure-activity data.
