ABSTRACT
Since the advent of antibody checkpoint inhibitors as highly efficient drugs for cancer treatment, the development of immunomodulating small molecules in oncology has gained great attention. Drug candidates targeting IDO1, a key enzyme in tryptophan metabolism, are currently under clinical investigation in combination with PD-1/PD-L1 agents as well as with other established anti-tumor therapeutics. A ligand based design approach from hydroxyamidine 4 that aimed at heme-binding IDO1 inhibitors resulted in new compounds with moderate IDO1 potency. A hybrid structure design that made use of the linrodostat structure (2) led to oxalamide derived, heme-displacing IDO1 inhibitors with high cell-based IDO1 potency and a favorable ADME/PK profile.
Subject(s)
Amides/pharmacology , Drug Discovery , Enzyme Inhibitors/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Oxamic Acid/pharmacology , Amides/chemical synthesis , Amides/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Molecular Structure , Oxamic Acid/chemical synthesis , Oxamic Acid/chemistry , Structure-Activity RelationshipABSTRACT
Through structural modification of an oxalamide derived chemotype, a novel class of highly potent, orally bioavailable IDO1-specific inhibitors was identified. Representative compound 18 inhibited human IDO1 with IC50 values of 3.9 nM and 52 nM in a cellular and human whole blood assay, respectively. In vitro assessment of the ADME properties of 18 demonstrated very high metabolic stability. Pharmacokinetic profiling in mice showed a significantly reduced clearance compared to the oxalamides. In a mouse pharmacodynamic model 18 nearly completely suppressed lipopolysaccharide-induced kynurenine production. Hepatocyte data of 18 suggest the human clearance to be in a similar range to linrodostat (1).
Subject(s)
Amides/pharmacology , Bridged Bicyclo Compounds/pharmacology , Drug Discovery , Enzyme Inhibitors/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Oxamic Acid/pharmacology , Amides/chemical synthesis , Amides/chemistry , Animals , Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Kynurenine/antagonists & inhibitors , Kynurenine/biosynthesis , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Mice , Molecular Structure , Oxamic Acid/chemical synthesis , Oxamic Acid/chemistry , Structure-Activity RelationshipABSTRACT
Following the impressive success of checkpoint inhibitors in the treatment of cancer, combinations of IDO1 inhibitors with PD-1/PD-L1 antibodies are in clinical development aiming to increase response rates. Using the hydroxyamidine pharmacophore of the IDO1 inhibitor INCB14943 as a starting point for the design of new inhibitors, the potential shortcomings of extensive hydroxyamidine glucuronidation in humans was addressed. Compounds were optimized using a stability assay with recombinant UGT1A9 enzyme together with the measurement of glucuronide formation in human hepatocytes. Optimized analog 24 showed cellular and biochemical IDO1 IC50 values in the low nanomolar range, a suitable in vitro ADME/PK profile, and efficacy in an animal model of cancer. In a humanized liver mouse model the lead compound exhibited significantly reduced glucuronidation compared to epacadostat (2).
