459448-06-7Relevant articles and documents
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
, 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.
Triazolopyridinylsulfanyl derivatives as p38 MAP kinase inhibitors
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Page/Page column 31, (2008/06/13)
A compound of formula (I), or a pharmaceutically acceptable salt and/or solvate (including hydrate) thereof; and the use of a compound of formula (I) 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 airways diseases, more particularly obstructive or inflammatory airways diseases, preferably chronic obstructive pulmonary disease.
NOVEL PROCESSES AND INTERMEDIATES FOR PREPARING TRIAZOLO-PYRIDINES
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Page 46, (2010/02/06)
The present invention relates and intermediates to a novel process for preparing triazolo-pyridines of the formula I wherein R1 is selected from the group consisting of hydrogen, (C,-C6)alkyl or other suitable substituents; R3 is selected from the group consisting óf hydrogen, (Cl-C6)alkyl or other suitable substituents; s is an integer from 0-5; R4is hydrogen or a suitable substituent and to intermediates for their preparation. The compounds prepared by the methods of the present invention are potent inhibitors of MAP kinases, preferably p38 kinase. They are useful in the treatment of inflammation, osteoarthritis, rheumatoid arthritis, cancer, reperfusion or ischemia in stroke or heart attack, autoimmune diseases and other disorders.
