2. Academic Validation
  3. Mitigation of cardiovascular toxicity in a series of CSF-1R inhibitors, and the identification of AZD7507

Mitigation of cardiovascular toxicity in a series of CSF-1R inhibitors, and the identification of AZD7507

  • Bioorg Med Chem Lett. 2013 Aug 15;23(16):4591-6. doi: 10.1016/j.bmcl.2013.06.031.
David A Scott 1,  Les A Dakin,  Kevin Daly,  David J Del Valle,  R Bruce Diebold,  Lisa Drew,  Jayachandran Ezhuthachan,  Thomas W Gero,  Claude A Ogoe,  Charles A Omer,  Sean P Redmond,  Galina Repik,  Kumar Thakur,  Qing Ye,  Xiaolan Zheng
Affiliations

Affiliation

  • 1 AstraZeneca R&D Boston, Oncology iMED, 35 Gatehouse Drive, Waltham, MA 02451, USA. Electronic address: david.scott@astrazeneca.com.
PMID: 23842474 DOI: 10.1016/j.bmcl.2013.06.031
Abstract

The potent and selective 3-amido-4-anilinoquinoline CSF-1R inhibitor AZ683 suffered from cardiovascular liabilities, which were linked to the off-target activities of the compound and ion channel activity in particular. Less basic and less lipophilic examples from both the quinoline and cinnoline series demonstrated cleaner secondary pharmacology profiles. Cinnoline 31 retained the required potency and oral PK profile, and was progressed through the safety screening cascade to be nominated into development as AZD7507.

Keywords

CSF-1R; Inhibitor; Kinase.

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