ABSTRACT
A series of ß-aminoacyl containing thiazolidine derivatives was synthesized and evaluated for their ability to inhibit DPP-IV. Several thiazolidine derivatives with an acid moiety were found to be potent DPP-IV inhibitors. Among them, compound 2da is the most active in this series with an IC(50) value of 1 nM, and it showed excellent selectivity over DPP-IV related enzymes including DPP-2, DPP-8, and DPP-9. Compound 2da is chemically and metabolically stable, and showed no CYP inhibition, hERG binding or cytotoxicity. Compound 2db, an ester prodrug of 2da, showed good in vivo DPP-IV inhibition after oral administration in rat and dog models.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Thiazolidines/chemical synthesis , Administration, Oral , Animals , Crystallography, X-Ray , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Disease Models, Animal , Dogs , Enzyme Activation/drug effects , Inhibitory Concentration 50 , Molecular Structure , Rats , Thiazolidines/chemistry , Thiazolidines/pharmacologyABSTRACT
Compounds with homopiperazine skeleton are designed to find a potent DPP-IV inhibitor without inhibiting CYP. Thus a series of beta-aminoacyl-containing homopiperazine derivatives was synthesized and evaluated. Compounds with acid moiety were found to be potent inhibitors of DPP-IV without inhibiting CYP 3A4. More specifically, compound 7m showed nanomolar activity with no inhibition towards five subtypes of CYPs, was considered as a prototype for further derivatization. Based on its X-ray co-crystal structure with human DPP-IV, we identified compounds 7s and 7t which showed good in vitro activity, no CYP inhibition, and good selectivity.
Subject(s)
Chemistry, Pharmaceutical/methods , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Piperazines/chemistry , Binding Sites , Crystallography, X-Ray/methods , Cytochrome P-450 CYP3A/chemistry , Diabetes Mellitus/drug therapy , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Structure , Piperazine , Pyrazines/pharmacology , Sitagliptin Phosphate , Structure-Activity Relationship , Triazoles/pharmacologyABSTRACT
A series of novel indene N-oxide derivatives were prepared by various synthetic methods and evaluated for their ability to activate PPARgamma. The best PPARgamma agonist in this series was 9h, which showed an EC(50) value of 15 nM.
Subject(s)
Indenes/chemistry , Indenes/pharmacology , PPAR gamma/agonists , Structure-Activity RelationshipABSTRACT
Inhibitors of dipeptidyl peptidase IV (DPP-IV) have been shown to be effective treatments for type 2 diabetes. A series of beta-aminoacyl-containing cyclic hydrazine derivatives were synthesized and evaluated as DPP-IV inhibitors. One member of this series, (R)-3-amino-1-(2-benzoyl-1,2-diazepan-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one (10f), showed potent in vitro activity, good selectivity and in vivo efficacy in mouse models. Also, the binding mode of compound 10f was determined by X-ray crystallography.
Subject(s)
Chemistry, Pharmaceutical/methods , Dipeptidyl-Peptidase IV Inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Hydrazines/chemical synthesis , Animals , Crystallography, X-Ray , Drug Design , Glucagon-Like Peptide 1/metabolism , Hydrazines/pharmacology , Inhibitory Concentration 50 , Kinetics , Mice , Mice, Inbred C57BL , Models, Chemical , Molecular Conformation , Protein Structure, TertiaryABSTRACT
Agonists of peroxisome proliferator-activated receptor gamma (PPAR gamma) are of interest as a treatment for diabetes, which prompted the identification of a new class of non-TZD PPAR gamma agonist. Moreover, compound 14c has displayed the most active agonistic activity with an EC50 value of 50 nM, in addition to exhibiting a new binding mode in the X-ray cocrystal structure.