ABSTRACT
This paper describes the identification and optimization of a novel series of DFG-out binding p38 inhibitors as inhaled agents for the treatment of chronic obstructive pulmonary disease. Structure based drug design and "inhalation by design" principles have been applied to the optimization of the lead series exemplied by compound 1a. Analogues have been designed to be potent and selective for p38, with an emphasis on slow enzyme dissociation kinetics to deliver prolonged lung p38 inhibition. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimize systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance and glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimize drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity, and solubility were considered to ensure compatibility with a dry powder inhaler. 1ab (PF-03715455) was subsequently identified as a clinical candidate from this series with efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of COPD.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Azabicyclo Compounds/chemical synthesis , Methylurea Compounds/chemical synthesis , Pulmonary Disease, Chronic Obstructive/drug therapy , Pyrazoles/chemical synthesis , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Administration, Inhalation , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Azabicyclo Compounds/pharmacokinetics , Azabicyclo Compounds/pharmacology , Binding Sites , Cell Membrane Permeability , Crystallography, X-Ray , Dogs , Drug Stability , Humans , In Vitro Techniques , Kinetics , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Methylurea Compounds/pharmacokinetics , Methylurea Compounds/pharmacology , Models, Molecular , Protein Binding , Protein Conformation , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Rats , Solubility , Surface Plasmon Resonance , Tumor Necrosis Factor-alpha/biosynthesis , p38 Mitogen-Activated Protein Kinases/chemistryABSTRACT
A sulfur HASC (alpha-hetero-atom substituted carbonyl) linker has been utilized in solid-phase approaches to oxindoles and tetrahydroquinolones. The route to oxindoles employs the first Pummerer cyclizations on solid phase, whereas the route to tetrahydroquinolones involves a microwave-assisted Heck reaction followed by a Michael cyclization. In both cases, the linker is cleaved in a traceless fashion by electron transfer from samarium(II) iodide. The routes illustrate the compatibility of the linker system with a number of reaction types and its utility for library synthesis.
Subject(s)
Cross-Linking Reagents/chemistry , Heterocyclic Compounds/chemical synthesis , Iodides/chemistry , Samarium/chemistry , Sulfur/chemistry , Cyclization , Heterocyclic Compounds/chemistry , Indoles/chemistry , Molecular Structure , OxindolesABSTRACT
[reaction: see text] A sulfur alpha-heteroatom-substituted carbonyl (HASC) linker has been utilized in a solid-phase approach to tetrahydroquinolones. The route illustrates the compatibility of the linker system with palladium-catalyzed transformations and its utility for library synthesis. The linker is cleaved by electron transfer from samarium(II) iodide.