7-(Pyrazol-4-yl)-3H-imidazo[4, 5-b]pyridine-based derivatives for kinase inhibition: Co-crystallisation studies with Aurora-A reveal distinct differences in the orientation of the pyrazole N1-substituent. Issue 19 (1st October 2015)

• Record Type: Journal Article
• Authors: Bavetsias, Vassilios; Pérez-Fuertes, Yolanda; McIntyre, Patrick J.; Atrash, Butrus; Kosmopoulou, Magda; O'Fee, Lisa; Burke, Rosemary; Sun, Chongbo; Faisal, Amir; Bush, Katherine; Avery, Sian; Henley, Alan; Raynaud, Florence I.; Linardopoulos, Spiros; Bayliss, Richard; Blagg, Julian
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 19(2015)
• Page Start: 4203
• Page End: 4209
• Publication Date: 2015-10-01
• Subjects: Aurora-A -- Imidazo[4, 5-b]pyridine -- Aurora kinase; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.08.003
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Introduction of a 1-benzyl-1 H -pyrazol-4-yl moiety at C7 of the imidazo[4, 5- b ]pyridine scaffold provided7a which inhibited a range of kinases including Aurora-A. Modification of the benzyl group in7a, and subsequent co-crystallisation of the resulting analogues with Aurora-A indicated distinct differences in binding mode dependent upon the pyrazole N -substituent. Compounds7a and14d interact with the P-loop whereas14a and14b engage with Thr217 in the post-hinge region. These crystallographic insights provide options for the design of compounds interacting with the DFG motif or with Thr217.