Identification of novel p38alpha MAP kinase inhibitors using fragment-based lead generation.

Article Details


Gill AL, Frederickson M, Cleasby A, Woodhead SJ, Carr MG, Woodhead AJ, Walker MT, Congreve MS, Devine LA, Tisi D, O'Reilly M, Seavers LC, Davis DJ, Curry J, Anthony R, Padova A, Murray CW, Carr RA, Jhoti H

Identification of novel p38alpha MAP kinase inhibitors using fragment-based lead generation.

J Med Chem. 2005 Jan 27;48(2):414-26.

PubMed ID
15658855 [ View in PubMed

We describe the structure-guided optimization of the molecular fragments 2-amino-3-benzyloxypyridine 1 (IC(50) 1.3 mM) and 3-(2-(4-pyridyl)ethyl)indole 2 (IC(50) 35 microM) identified using X-ray crystallographic screening of p38alpha MAP kinase. Using two separate case studies, the article focuses on the key compounds synthesized, the structure-activity relationships and the binding mode observations made during this optimization process, resulting in two potent lead series that demonstrate significant increases in activity. We describe the process of compound elaboration either through the growing out from fragments into adjacent pockets or through the conjoining of overlapping fragments and demonstrate that we have exploited the mobile conserved activation loop, consisting in part of Asp168-Phe169-Gly170 (DFG), to generate significant improvements in potency and kinase selectivity.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
3-(1-NAPHTHYLMETHOXY)PYRIDIN-2-AMINEMitogen-activated protein kinase 14IC 50 (nM)440007.422Details
3-(Benzyloxy)Pyridin-2-AmineMitogen-activated protein kinase 14IC 50 (nM)13000007.422Details
3-FLUORO-5-MORPHOLIN-4-YL-N-[1-(2-PYRIDIN-4-YLETHYL)-1H-INDOL-6-YL]BENZAMIDEMitogen-activated protein kinase 14IC 50 (nM)3407.422Details
3-FLUORO-5-MORPHOLIN-4-YL-N-[3-(2-PYRIDIN-4-YLETHYL)-1H-INDOL-5-YL]BENZAMIDEMitogen-activated protein kinase 14IC 50 (nM)6307.422Details
3-fluoro-N-1H-indol-5-yl-5-morpholin-4-ylbenzamideMitogen-activated protein kinase 14IC 50 (nM)1620007.422Details
Inhibitor of P38 KinaseMitogen-activated protein kinase 14IC 50 (nM)350007.422Details
N-(3-TERT-BUTYL-1H-PYRAZOL-5-YL)-N'-{4-CHLORO-3-[(PYRIDIN-3-YLOXY)METHYL]PHENYL}UREAMitogen-activated protein kinase 14IC 50 (nM)3507.422Details