2YIS

triazolopyridine inhibitors of p38 kinase.

Summary for 2YIS

• Entry DOI: 10.2210/pdb2yis/pdb
• Related: 1A9U 1BL6 1BL7 1BMK 1DI9 1IAN 1KV1 1KV2 1M7Q 1OUK 1OUY 1OVE 1OZ1 1R39 1R3C 1W7H 1W82 1W83 1W84 1WBN 1WBO 1WBS 1WBT 1WBV 1WBW 1WFC 1YQJ 1ZYJ 1ZZ2 1ZZL 2BAJ 2BAK 2BAL 2BAQ 2I0H 2Y8O 2YIW 2YIX
• Descriptor: MITOGEN-ACTIVATED PROTEIN KINASE 14, 1-[3-tert-butyl-1-(3-chloro-4-hydroxyphenyl)-1H-pyrazol-5-yl]-3-{2-[(3-{2-[(2-hydroxyethyl)sulfanyl]phenyl}[1,2,4]triazolo[4,3-a]pyridin-6-yl)sulfanyl]benzyl}urea, 2-fluoro-4-[4-(4-fluorophenyl)-1H-pyrazol-3-yl]pyridine, ... (4 entities in total)
• Functional Keywords: transferase, inhibitor sbdd kinase, cell cycle
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm (By similarity): Q16539
• Total number of polymer chains: 1
• Total formula weight: 42169.51

Authors

Millan, D.S.,Anderson, M.,Bazin, R.,Bunnage, M.E.,Burrows, J.L.,Butcher, K.J.,Dodd, P.G.,Evans, T.J.,Fairman, D.A.,Hughes, S.J.,Irving, S.L.,Kilty, I.C.,Lemaitre, A.,Lewthwaite, R.A.,Mahnke, A.,Mathais, J.P.,Philip, J.,Phillips, C.,Smith, R.T.,Stefaniack, M.H.,Yeadon, M. (deposition date: 2011-05-16, release date: 2011-11-30, Last modification date: 2024-05-08)

Primary citation

Millan, D.S.,Bunnage, M.E.,Burrows, J.L.,Butcher, K.J.,Dodd, P.G.,Evans, T.J.,Fairman, D.A.,Hughes, S.J.,Kilty, I.C.,Lemaitre, A.,Lewthwaite, R.A.,Mahnke, A.,Mathias, J.P.,Philip, J.,Smith, R.T.,Stefaniak, M.H.,Yeadon, M.,Phillips, C.
Design and Synthesis of Inhaled P38 Inhibitors for the Treatment of Chronic Obstructive Pulmonary Disease.
J.Med.Chem., 54:7797-, 2011

PubMed 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.

PubMed: 21888439
DOI: 10.1021/JM200677B

Experimental method

X-RAY DIFFRACTION (2 Å)