616243-06-2

Upstream product

• 5192-03-0 5-amino-1H-indole 
• 295311-40-9 3-fluoro-5-(4-morpholinyl)benzoic acid 

Relevant academic research and scientific papers

Identification of novel p38α MAP kinase inhibitors using fragment-based lead generation

We describe the structure-guided optimization of the molecular fragments 2-amino-3-benzyl-oxypyridine 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.

PHARMACEUTICAL COMPOUNDS

The invention provides a compound for use in the prophylaxis or treatment of a disease state or condition mediated by a p38 MAP kinase such as rheumatoid arthritis and osteoarthritis; the compound being of the general formula (I): wherein U, T, V and W are each a nitrogen atom or a group CR4 provided that no more than three of U, T, V and W are nitrogen atoms; R0 is hydrogen, C1-4 hydrocarbyl, halogen or a group -A-R3; R1 is hydrogen, C1-4 hydrocarbyl or a group -A-R3; provided that only one of R0 and R1 is a group -A-R3; R2 is hydrogen, C1-4 hydrocarbyl or halogen; A is a carbon- or heteroatom-containing linker group having a linking chain length of one or two atoms; R3 is a monocyclic or bicyclic heteroaryl group containing from five to twelve ring members; each group R4 is independently selected from hydrogen, hydroxy, halogen, nitro, cyano, a monocyclic heterocyclic group having up to seven ring members, a group N(R5)2, a group C(O)N(R6)2, a group S02N(R6)2, a group Ra-Rb and a group Y; provided that no more than one group Y is present; Ra is a bond, O, S, SO, S02, NH or N-C1-4 hydrocarbyl; Rb is C1-8 hydrocarbyl optionally interrupted by O, S, SO, SO2, NH or N-C1- 4 hydrocarbyl and optionally substituted by one or more substitutents selected from hydroxy, amino, mono- or di-C1-4 hydrocarbylamino, C1 -4 hydrocarbyloxy, oxo, C1 -4 hydrocarbylthio and halogen; each group R5 is independently selected from hydrogen, C1-4 alkyl, C1-4 acyl and C 1-4 alkylsulphonyl; each group R6 is independently selected from hydrogen and C1-4 hydrocarbyl; Y is a group -N(R7)-C(O)-R8 or -N(R7)_SO2-R8; R7 is hydrogen, C1-4 hydrocarbyl or a group C(O)-R8 or S02-R8; R8 is selected from C1-l0 hydrocarbyl, CI-10hydrocarbylamino, CI-10 hydrocarbylthio, C1-l0 hydrocarbyloxy, and aryl, arylamino, arylthio and aryloxy groups, the aryl moieties of which are carbocyclic or heterocyclic and have from five to twelve ring members, each substituent group R8 being optionally substituted by one or more groups R4 other than Y; or R7 and R8 together with the nitrogen and carbon or sulphur atoms to which they are attached are linked to form a ring structure of 4 to 7 ring members; wherein R0 is other than a 2-(2,4-diamino-6-triazinyl)ethyl group when, in combination, U, T, V and W are all CH, and R1 and R2 are both hydrogen; and provided that when the group -A-R3 contains an acidic substitituent group selected from carboxylic, phosphonic and sulphonic acids and tetrazoles, or contains a -C(O)NSO2- group, or when -A- is -C(O)N- and the nitrogen atom of the group A is linked directly to a furan or thiophene ring, then either R1 is -A-R3 and both R0 and R2 are hydrogen, or R0 is-A-R3 and R1 is hydrogen.