ABSTRACT
A series of peptidomimetic containing bidentate pTyr mimetics (9a-w) are reported as potent and selective PTP1B inhibitors. Compounds (9p and 9q) showed excellent selectivity towards PTP1B over various PTPs, including TCPTP (in vitro), which confirms discovery of highly potent and selective PTP1B inhibitors.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Peptidomimetics , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Acetates/chemistry , Amides/chemistry , Dipeptides/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Humans , Models, Molecular , Molecular Structure , Piperidines/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Pyrrolidine based peptidomimetics are reported as potent and selective DPP-IV inhibitors for the treatment of T2DM. Compounds 16c and 16d showed excellent in vitro potency and selectivity towards DPP-IV and the lead compound 16c showed sustained antihyperglycemic effects, along with improved pharmacokinetic profile.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Peptidomimetics/pharmacology , Animals , Dipeptidyl-Peptidase IV Inhibitors/pharmacokinetics , Mice , Mice, Inbred C57BL , Peptidomimetics/pharmacokineticsABSTRACT
A novel series of pTyr mimetics containing triaryl-sulfonamide derivatives (5a-r) are reported as potent and selective PTP1B inhibitors. Some of the test compounds (5o and 5p) showed excellent selectivity towards PTP1B over various PTPs, including TCPTP (in vitro). The lead compound 5o showed potent antidiabetic activity (in vivo), along with improved pharmacokinetic profile. These preliminary results confirm discovery of highly potent and selective PTP1B inhibitors for the treatment of T2DM.
Subject(s)
Diabetes Mellitus/drug therapy , Drug Discovery , Enzyme Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Sulfonamides/pharmacology , Administration, Oral , Animals , Biological Availability , Drug Evaluation, Preclinical , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/chemistry , Male , Mice , Mice, Inbred C57BL , Models, Molecular , Molecular Structure , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Structure-Activity Relationship , Sulfonamides/administration & dosage , Sulfonamides/chemistryABSTRACT
Two novel series of 5-nitro-2-phenoxybenzoic acid derivatives are designed as potent PAI-1 inhibitors using hybridization and conformational restriction strategy in the tiplaxtinin and piperazine chemo types. The lead compounds 5a, 6c, and 6e exhibited potent PAI-1 inhibitory activity and favorable oral bioavailability in the rodents.
