3-amido-4-anilinoquinolines as CSF-1R kinase inhibitors 2: Optimization of the PK profile.
The optimization of compounds from the 3-amido-4-anilinoquinolines series of CSF-1R kinase inhibitors is described. The series has excellent activity and kinase selectivity. Excellent physical properties and rodent PK profiles were achieved through the introduction of cyclic amines at the quinoline 6-position. Compounds with good activity in a mouse PD model measuring inhibition of pCSF-1R were identified.
Scott
David A
DA
Cancer Research, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. david.scott@astrazeneca.com
Bell
Kirsten J
KJ
Campbell
Cheryl T
CT
Cook
Donald J
DJ
Dakin
Les A
LA
Del Valle
David J
DJ
Drew
Lisa
L
Gero
Thomas W
TW
Hattersley
Maureen M
MM
Omer
Charles A
CA
Tyurin
Boris
B
Zheng
Xiaolan
X
D000588:Amines / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D051379:Mice; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D011804:Quinolines / Q000737:chemistry* / Q000493:pharmacokinetics*; D051381:Rats; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry*
D000588:Amines; D000970:Antineoplastic Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D016186:Receptor, Macrophage Colony-Stimulating Factor