Scaffold-hopping with zwitterionic CCR3 antagonists: identification and optimisation of a series with good potency and pharmacokinetics leading to the discovery of …

…, S Hawley, T Linannen, CA Luckhurst, T Mochel…

Index: Barton, Patrick; Caffrey, Moya V.; Linannen, Tero; Luckhurst, Christopher A.; Mochel, Tobias; Perry, Matthew W. D.; Springthorpe, Brian; Stein, Linda; Bahl, Ash; Bowers, Keith; Gilmour, Peter; Hawley, Shaun; Denton, Rebecca; Riley, Robert J.; Roe, Emma; Webborn, Peter Bioorganic and Medicinal Chemistry Letters, 2012 , vol. 22, # 21 p. 6694 - 6699,6

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Citation Number: 8

Abstract

We have described our earlier work on CCR3/H 1 dual antagonists that lead to the discovery of AZ10565259 (1). 13 Activity at hERG was a major issue in this series that was overcome by the addition of an acidic centre making the molecules zwitterionic. The addition of the acidic centre to the molecule resulted in reduced bioavailability that was affected by poor solubility and proved to be dependent on physical form. Whilst 1 progressed into Early Development, work was ...