ABSTRACT
3-amido-4-anilinoquinolines are potent and highly selective inhibitors of CSF-1R. Their synthesis and SAR is reported, along with initial efforts to optimize the physical properties and PK through modifications at the quinoline 6- and 7-positions.
Subject(s)
Chemistry, Pharmaceutical/methods , Neoplasms/drug therapy , Quinolines/chemistry , Quinolines/pharmacokinetics , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Receptor, Macrophage Colony-Stimulating Factor/chemistry , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Drug Design , Humans , Inhibitory Concentration 50 , Kinetics , Models, Chemical , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , RatsABSTRACT
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.
Subject(s)
Chemistry, Pharmaceutical/methods , Neoplasms/drug therapy , Quinolines/chemistry , Quinolines/pharmacokinetics , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Receptor, Macrophage Colony-Stimulating Factor/chemistry , Amines/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Inhibitory Concentration 50 , Kinetics , Mice , Models, Chemical , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , RatsABSTRACT
A series of amidoheteroaryl compounds were designed and synthesized as inhibitors of B-Raf kinase. Several compounds from the series show excellent potency in biochemical, phenotypic and mode of action cellular assays. Potent examples from the series have also demonstrated good plasma exposure following an oral dose in rodents and activity against the Ras-Raf pathway in tumor bearing mice.
Subject(s)
Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/chemical synthesis , Mutation , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Administration, Oral , Animals , Drug Design , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Mice , Models, Chemical , Rats , Structure-Activity Relationship , raf Kinases/metabolism , ras Proteins/metabolismABSTRACT
The bisamide class of kinase inhibitors was identified as being active against CSF-1R. The synthesis and SAR of pyridyl and thiazolyl bisamides are reported, along with the pharmacokinetic properties and in vivo activity of selected examples.