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Article

Identification of Novel p38α MAP Kinase Inhibitors Using Fragment-Based Lead Generation

Adrian L. Gill,^†* Martyn Frederickson,^† Anne Cleasby,^‡ Steven J. Woodhead,^† Maria G. Carr,^† Andrew J. Woodhead,^† Margaret T. Walker,^† Miles S. Congreve,^† Lindsay A. Devine,^‡ Dominic Tisi, Marc O'Reilly,^‡ Lisa C. A. Seavers, Deborah J. Davis, Jayne Curry, Rachel Anthony, Alessandro Padova,^§ Christopher W. Murray,^§ Robin A. E. Carr,^† and Harren Jhoti^‡

Astex Technology, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom

J. Med. Chem., 2005, 48 (2), pp 414–426

DOI: 10.1021/jm049575n

Publication Date (Web): December 21, 2004

†

Medicinal Chemistry group.

To whom correspondence should be addressed. Phone: +44 (0)1223 226281; Fax +44 (0)1223 226201; E-mail: a.gill@astex-technology.com.

‡

Protein Structure group.

Protein Technology group.

Biology group.

Computational Chemistry and Informatics group.

Current address: C4T, Colosseum Combinatorial Chemistry Centre for Technology, University of Rome ‘Tor Vergata', Rome, Italy.

Abstract

We describe the structure-guided optimization of the molecular fragments 2-amino-3-benzyloxypyridine 1 (IC₅₀ 1.3 mM) and 3-(2-(4-pyridyl)ethyl)indole 2 (IC₅₀ 35 μM) identified using X-ray crystallographic screening of p38α 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.

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