ABSTRACT
High throughput screening (HTS) of our compound file provided an attractive lead compound with modest P2X(7) receptor antagonist potency and high selectivity against a panel of receptors and channels, but also with high human plasma protein binding and a predicted short half-life in humans. Multi-parameter optimization was used to address the potency, physicochemical and pharmacokinetic properties which led to potent P2X(7)R antagonists with good disposition properties. Compound 33 (CE-224,535) was advanced to clinical studies for the treatment of rheumatoid arthritis.
Subject(s)
Benzamides , Drug Discovery , Purinergic P2 Receptor Antagonists , Receptors, Purinergic P2X7/metabolism , Uracil/analogs & derivatives , Administration, Oral , Animals , Antirheumatic Agents/chemical synthesis , Antirheumatic Agents/chemistry , Antirheumatic Agents/pharmacokinetics , Antirheumatic Agents/pharmacology , Benzamides/chemical synthesis , Benzamides/chemistry , Benzamides/pharmacokinetics , Benzamides/pharmacology , Humans , Inhibitory Concentration 50 , Molecular Structure , Protein Binding/drug effects , Purinergic P2 Receptor Antagonists/chemical synthesis , Purinergic P2 Receptor Antagonists/chemistry , Purinergic P2 Receptor Antagonists/pharmacokinetics , Purinergic P2 Receptor Antagonists/pharmacology , Rats , Structure-Activity Relationship , Uracil/chemical synthesis , Uracil/chemistry , Uracil/pharmacokinetics , Uracil/pharmacologyABSTRACT
The discovery, synthesis and SAR of a novel series of 3-benzyl-1,3-oxazolidin-2-ones as positive allosteric modulators (PAMs) of mGluR2 is described. Expedient hit-to-lead work on a single HTS hit led to the identification of a ligand-efficient and structurally attractive series of mGluR2 PAMs. Human microsomal clearance and suboptimal physicochemical properties of the initial lead were improved to give potent, metabolically stable and orally available mGluR2 PAMs.
Subject(s)
Carbamates/chemistry , Oxazolidinones/chemical synthesis , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Receptors, Metabotropic Glutamate/chemistry , Schizophrenia/drug therapy , Administration, Oral , Allosteric Regulation , Allosteric Site , Chemistry, Pharmaceutical/methods , Drug Design , Humans , Inhibitory Concentration 50 , Ligands , Microsomes/metabolism , Models, Chemical , Molecular Structure , Oxazolidinones/chemistryABSTRACT
The potency and physical properties of a previously reported 7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine series of human eosinophil phosphodiesterase inhibitors were improved by tying the lactam moiety into a triazolo ring. The resulting 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridine series provided nonionizable analogs with melting point properties suitable for micronization. Substitution at the 3-position of the 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridine tricycle led to a 2-thienyl analog, 19 (tofimilast), a potent PDE4 inhibitor with low oral bioavailability and no emesis-associated behaviors in ferrets at plasma concentrations up to 152 ng/mL.
