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

DA Scott, LA Dakin, K Daly, DJ Del Valle… - Bioorganic & medicinal …, 2013 - Elsevier
DA Scott, LA Dakin, K Daly, DJ Del Valle, RB Diebold, L Drew, J Ezhuthachan, TW Gero…
Bioorganic & medicinal chemistry letters, 2013Elsevier
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.
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.
Elsevier