ABSTRACT
The successful launches of dipeptidyl peptidase IV (DPP IV) inhibitors as oral anti-diabetics warrant and spur the further quest for additional chemical entities in this promising class of therapeutics. Numerous pharmaceutical companies have pursued their proprietary candidates towards the clinic, resulting in a large body of published chemical structures associated with DPP IV. Herein, we report the discovery of a novel chemotype for DPP IV inhibition based on the C-(1-aryl-cyclohexyl)-methylamine scaffold and its optimization to compounds which selectively inhibit DPP IV at low-nM potency and exhibit an excellent oral pharmacokinetic profile in the rat.
Subject(s)
Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Dipeptidyl-Peptidase IV Inhibitors/pharmacokinetics , Drug Discovery , Methylamines/chemical synthesis , Methylamines/pharmacokinetics , Adamantane/analogs & derivatives , Adamantane/chemistry , Adamantane/pharmacology , Administration, Oral , Animals , Caco-2 Cells , Crystallography, X-Ray , Cyclization , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Enzyme Activation/drug effects , Humans , Inhibitory Concentration 50 , Methylamines/chemistry , Methylamines/pharmacology , Molecular Structure , Nitriles/chemistry , Nitriles/pharmacology , Pyrazines/chemistry , Pyrazines/pharmacology , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Rats , Sitagliptin Phosphate , Triazoles/chemistry , Triazoles/pharmacology , VildagliptinABSTRACT
Novel deazaxanthine-based DPP-4 inhibitors have been identified that are potent (IC(50) <10nM) and highly selective versus other dipeptidyl peptidases. Their synthesis and SAR are reported, along with initial efforts to improve the PK profile through decoration of the deazaxanthine core. Optimisation of compound 3a resulted in the identification of compound (S)-4i, which displayed an improved in vitro and ADME profile. Further enhancements to the PK profile were possible by changing from the deazahypoxanthine to the deazaxanthine template, culminating in compound 12g, which displayed good ex vivo DPP-4 inhibition and a superior PK profile in rat, suggestive of once daily dosing in man.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Animals , Caco-2 Cells , Crystallography, X-Ray , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Enzyme Activation/drug effects , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Heterocyclic Compounds/therapeutic use , Humans , Inhibitory Concentration 50 , Male , Models, Molecular , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
Tryptase is a serine protease found almost exclusively in mast cells. It has trypsin-like specificity, favoring cleavage of substrates with an arginine (or lysine) at the P1 position, and has optimal catalytic activity at neutral pH. Current evidence suggests tryptase beta is the most important form released during mast cell activation in allergic diseases. It is shown to have numerous pro-inflammatory cellular activities in vitro, and in animal models tryptase provokes broncho-constriction and induces a cellular inflammatory infiltrate characteristic of human asthma. Screening of in-house inhibitors of factor Xa (a closely related serine protease) identified beta-amidoester benzamidines as potent inhibitors of recombinant human betaII tryptase. X-ray structure driven template modification and exchange of the benzamidine to optimize potency and pharmacokinetic properties gave selective, potent and orally bioavailable 4-(3-aminomethyl phenyl)piperidinyl-1-amides.
Subject(s)
Amides , Piperidines , Serine Endopeptidases/drug effects , Administration, Oral , Amides/chemical synthesis , Amides/chemistry , Amides/pharmacology , Animals , Biological Availability , Caco-2 Cells , Crystallography, X-Ray , Drug Design , Factor Xa Inhibitors , Humans , Liver/enzymology , Models, Molecular , Molecular Structure , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/pharmacology , Protein Conformation , Rats , Recombinant Proteins/drug effects , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship , TryptasesABSTRACT
The utilization and impact of parallel synthesis on lead exploration around initial hit oxindole (1) are described. The emergent SAR, analogue design and functional impact will also be detailed.
