ABSTRACT
Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.
Subject(s)
Indazoles/chemistry , Oxazoles/chemistry , Phosphoinositide-3 Kinase Inhibitors , Respiratory Tract Diseases/drug therapy , Sulfonamides/chemistry , Administration, Inhalation , Animals , Asthma/drug therapy , Female , Humans , Indazoles/pharmacokinetics , Indazoles/pharmacology , Indoles , Isoenzymes/antagonists & inhibitors , Male , Microsomes/metabolism , Molecular Docking Simulation , Ovalbumin/immunology , Oxazoles/pharmacokinetics , Oxazoles/pharmacology , Piperazines , Pneumonia/drug therapy , Pneumonia/immunology , Pulmonary Disease, Chronic Obstructive/drug therapy , Rabbits , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacology , Th2 Cells/immunologyABSTRACT
Using a pyrrolidine-5,5-trans-lactam template, we have designed small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. Compound 11a, with an alpha-ethyl P1 substituent and a Boc-valine substituent at the pyrrolidine nitrogen, has an IC(50)=30 microM.
