ABSTRACT
A novel series of imidazoisoindoles were identified as potent indoleamine-2,3-dioxygenase (IDO) inhibitors. Lead optimization toward improving potency and eliminating CYP inhibition resulted in the discovery of lead compound 25, a highly potent IDO inhibitor with favorable pharmacokinetic properties. In the MC38 xenograft model in hPD-1 transgenic mice, 25 in combination with the anti-PD-1 monoclonal antibody (SHR-1210) achieved a synergistic antitumor effect superior to each single agent.
ABSTRACT
The MAPK pathway is identified as one of the most important pathways involved in cell proliferation and differentiation. A key kinase in the pathway, the Mitogen-activated protein kinase kinase (MEK) is recognized as a promising target for antitumor drugs. Structure-based design and optimization of known MEK inhibitors resulted in identification of compound 10a as a potent non-ATP competitive MEK inhibitor in both in vitro and in vivo tests.
Subject(s)
Antineoplastic Agents/pharmacology , Bridged Bicyclo Compounds/pharmacology , Drug Design , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Neoplasms, Experimental/drug therapy , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dogs , Dose-Response Relationship, Drug , HCT116 Cells , Humans , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Microsomes, Liver/metabolism , Mitogen-Activated Protein Kinase Kinases/metabolism , Models, Molecular , Molecular Structure , Neoplasms, Experimental/pathology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Rats , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
In this Letter we describe SAR investigation on the cyclopentyl-triazolol-pyrimidine scaffold in pursuit of new oral P2Y12 inhibitors. Different synthetic routes were developed for variations at the cyclopentyl core. Optimization finally led to compound 2d which was advanced into preclinical development based on better potency and safety profile in comparison to ticagrelor.