title: Identification of novel p38alpha MAP kinase inhibitors using fragment-based lead generation.
abstract: 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.
authors.affiliation: Astex Technology, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom. a.gill@astex-technology.com
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Gill
authors.forename: Martyn
authors.initials: M
authors.lastname: Frederickson
authors.forename: Anne
authors.initials: A
authors.lastname: Cleasby
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Woodhead
authors.forename: Maria G
authors.initials: MG
authors.lastname: Carr
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Woodhead
authors.forename: Margaret T
authors.initials: MT
authors.lastname: Walker
authors.forename: Miles S
authors.initials: MS
authors.lastname: Congreve
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Devine
authors.forename: Dominic
authors.initials: D
authors.lastname: Tisi
authors.forename: Marc
authors.initials: M
authors.lastname: O'Reilly
authors.forename: Lisa C A
authors.initials: LC
authors.lastname: Seavers
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Davis
authors.forename: Jayne
authors.initials: J
authors.lastname: Curry
authors.forename: Rachel
authors.initials: R
authors.lastname: Anthony
authors.forename: Alessandro
authors.initials: A
authors.lastname: Padova
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Murray
authors.forename: Robin A E
authors.initials: RA
authors.lastname: Carr
authors.forename: Harren
authors.initials: H
authors.lastname: Jhoti
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000631:Aminopyridines; D004791:Enzyme Inhibitors; D007211:Indoles; D008024:Ligands; D048051:p38 Mitogen-Activated Protein Kinases