title: Mitigation of cardiovascular toxicity in a series of CSF-1R inhibitors, and the identification of AZD7507.
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.
authors.affiliation: AstraZeneca R&D Boston, Oncology iMED, 35 Gatehouse Drive, Waltham, MA 02451, USA. Electronic address: david.scott@astrazeneca.com.
authors.forename: David A
authors.initials: DA
authors.lastname: Scott
authors.forename: Les A
authors.initials: LA
authors.lastname: Dakin
authors.forename: Kevin
authors.initials: K
authors.lastname: Daly
authors.forename: David J
authors.initials: DJ
authors.lastname: Del Valle
authors.forename: R Bruce
authors.initials: RB
authors.lastname: Diebold
authors.forename: Lisa
authors.initials: L
authors.lastname: Drew
authors.forename: Jayachandran
authors.initials: J
authors.lastname: Ezhuthachan
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Gero
authors.forename: Claude A
authors.initials: CA
authors.lastname: Ogoe
authors.forename: Charles A
authors.initials: CA
authors.lastname: Omer
authors.forename: Sean P
authors.initials: SP
authors.lastname: Redmond
authors.forename: Galina
authors.initials: G
authors.lastname: Repik
authors.forename: Kumar
authors.initials: K
authors.lastname: Thakur
authors.forename: Qing
authors.initials: Q
authors.lastname: Ye
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Zheng
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects*; D002478:Cells, Cultured; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D006168:Guinea Pigs; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D032383:Myocytes, Cardiac / Q000187:drug effects; D051381:Rats; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*
chemical_list: C585974:AZ683; C585975:AZD7507; D000634:Aminoquinolines; D000814:Aniline Compounds; D004791:Enzyme Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D016186:Receptor, Macrophage Colony-Stimulating Factor
keywords: CSF-1R; Inhibitor; Kinase