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
In this Letter, we present the results of a hit-finding and lead optimization programme against the EP4 receptor (EP4R). In a short time period, we were able to discover five structurally diverse series of hit compounds using a combination of virtual screening methods. The most favoured hit, compound 6, was demonstrated to be a competitive antagonist of the EP4R. Compound 73 was identified following several rounds of optimization, which centred on improving both the primary EP4R affinity and selectivity against the related EP2R as well as the aqueous solubility. This work culminated in the preparation of PGN-1531, the sodium salt of 73, which showed a marked improvement in solubility (>10 mg/mL). PGN-1531 is a potent and selective antagonist at EP4Rs in vitro and in vivo, with the potential to alleviate the symptoms of migraine that result from cerebral vasodilatation.
Subject(s)
Drug Discovery , Receptors, Prostaglandin E, EP4 Subtype/antagonists & inhibitors , Brain/blood supply , HEK293 Cells , Humans , Ligands , Migraine Disorders/drug therapy , Models, Molecular , Receptors, Prostaglandin E, EP4 Subtype/metabolism , Vasodilation/drug effectsABSTRACT
We report the optimization of a series of non-steroidal GR antagonists that led to the identification of compound 7. This compound is efficacious when dosed orally in an olanzapine-induced weight gain model in rats.
Subject(s)
Benzodiazepines/pharmacology , Drug Discovery , Receptors, Glucocorticoid/antagonists & inhibitors , Thymine/analogs & derivatives , Weight Gain/drug effects , Administration, Oral , Animals , Benzodiazepines/administration & dosage , Benzodiazepines/chemistry , Dose-Response Relationship, Drug , Models, Animal , Molecular Structure , Olanzapine , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Thymine/administration & dosage , Thymine/chemistry , Thymine/pharmacologyABSTRACT
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.