ABSTRACT
The genome of pancreatic ductal adenocarcinoma (PDAC) is associated with frequent deletion of the tumor suppressor gene SMAD family member 4 (SMAD4) with collateral deletion of its chromosomal neighbor malic enzyme 2 (ME2). In SMAD4 -/- /ME2 -/- PDAC cells, ME3 takes over the function of the ME2 enzyme, and hence therapeutic targeting of ME3 is expected to arrest tumor growth. Hitherto no selective small molecule inhibitor of ME3 has been reported in the context of PDAC. Based on the molecular docking studies and structure-activity relationships with the reported ME1 inhibitor, several analogues of 6-piperazin-1-ylpyridin-3-ol amides have been synthesized and screened for their ME inhibition activity. Among them, compound 16b is identified as the most potent and selective ME3 inhibitor with an IC50 of 0.15 µM on ME3, and with 15- and 9-fold selectivity over ME1 and ME2, respectively. In the cell viability assay, compound 16b exhibited an IC50 of 3.5 µM on ME2-null PDAC cells, viz., BxPC-3.
ABSTRACT
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.
Subject(s)
Benzoates/chemistry , Benzoates/pharmacology , Drug Design , Drug Discovery , Phenyl Ethers/chemistry , Plasminogen Activator Inhibitor 1/metabolism , Administration, Oral , Animals , Benzoates/pharmacokinetics , Biological Availability , Disease Models, Animal , Drug Evaluation, Preclinical , Indoleacetic Acids/chemistry , Indoleacetic Acids/pharmacology , Male , Molecular Structure , Phenyl Ethers/pharmacokinetics , Phenyl Ethers/pharmacology , Piperazine , Piperazines/chemistry , Rats , Rats, Wistar , Structure-Activity Relationship , Thrombosis/chemically induced , Thrombosis/drug therapyABSTRACT
A number of oxalamide derivatives have been synthesized and evaluated for PAI-1 inhibitory activity. In vitro PAI-1 inhibitory activities of oxalamide derivatives are evaluated by chromogenic assay. Few compounds have shown significant PAI-1 inhibitory activity.