Continued exploration of the triazolopyridine scaffold as a platform for p38 MAP kinase inhibition.
The structure based drug design, synthesis and structure-activity relationship of a series of C6 sulfur linked triazolopyridine based p38 inhibitors are described. The metabolic deficiencies of this series were overcome through changes in the C6 linker from sulfur to methylene, which was predicted by molecular modeling to be bioisosteric. X-ray of the ethylene linked compound 61 confirmed the predicted binding orientation of the scaffold in the p38 enzyme.
Jerome
Kevin D
KD
Pfizer Global Research and Development, St. Louis Laboratories, 700 Chesterfield Pkwy. W., Chesterfield, MO 63017, USA. kevin.d.jerome@pfizer.com
Rucker
Paul V
PV
Xing
Li
L
Shieh
Huey S
HS
Baldus
John E
JE
Selness
Shaun R
SR
Letavic
Michael A
MA
Braganza
John F
JF
McClure
Kim F
KF
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D008956:Models, Chemical; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D014230:Triazoles; D048051:p38 Mitogen-Activated Protein Kinases