945994-98-9Relevant academic research and scientific papers
Design and synthesis of inhaled p38 inhibitors for the treatment of chronic obstructive pulmonary disease
Millan, David S.,Bunnage, Mark E.,Burrows, Jane L.,Butcher, Kenneth J.,Dodd, Peter G.,Evans, Timothy J.,Fairman, David A.,Hughes, Samantha J.,Kilty, Iain C.,Lemaitre, Arnaud,Lewthwaite, Russell A.,Mahnke, Axel,Mathias, John P.,Philip, James,Smith, Robert T.,Stefaniak, Mark H.,Yeadon, Michael,Phillips, Christopher
experimental part, p. 7797 - 7814 (2012/01/05)
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.
TRIAZOLOPYRIDINE COMPOUNDS
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Page/Page column 42, (2008/06/13)
A compound of formula (Ia): or a pharmaceutically acceptable salt and/or solvate (including hydrate) thereof, or a compound of formula (Ib): or a pharmaceutically acceptable salt and/or solvate (including hydrate) thereof, and the use of a compound of formula (Ia) or (Ib) in the treatment of a TNF -mediated disease, disorder, or condition, or a p38 -mediated disease,. disorder, or condition, in particular the allergic and non-allergic airway diseases, more particularly obstructive or inflammatory airways diseases, preferably chronic obstructive pulmonary disease.
PYRIDINONE PYRAZOLE UREA AND PYRIMIDINONE PYRAZOLE UREA DERIVATIVES
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Page/Page column 72, (2008/06/13)
This invention is directed generally to substituted pyridinone and pyrimidinone compounds that generally inhibit p38 kinase, TNF, and/or cyclooxygeπase activity. Such substituted pyridinone and pyrimidinone compounds include compounds generally corresponding in structure to the following formula: wherein Z, n, R1, R2a, R2b, R2c, R2d, R2e, R3a, R3b R3c, R3d, R4, R5, R6, R7a, R7b, R7c, R7d and R7e are as defined in this specification. This invention also is directed to compositions of such substituted pyridinones and pyrimidinones (particularly pharmaceutical compositions), and methods for treating disorders (typically pathological disorders) associated with p38 kinase activity, TNF activity, and/or cyclooxygenase-2 activity.
