120418-62-4Relevant articles and documents
Discovery of Aminopyrazole Derivatives as Potent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR2 and 3
Brawn, Ryan A.,Cook, Andrew,Omoto, Kiyoyuki,Ke, Jiyuan,Karr, Craig,Colombo, Federico,Virrankoski, Milena,Prajapati, Sudeep,Reynolds, Dominic,Bolduc, David M.,Nguyen, Tuong-Vi,Gee, Patricia,Borrelli, Deanna,Caleb, Benjamin,Yao, Shihua,Irwin, Sean,Larsen, Nicholas A.,Selvaraj, Anand,Zhao, Xuesong,Ioannidis, Stephanos
supporting information, p. 93 - 98 (2020/12/21)
Fibroblast growth factor receptors (FGFR) 2 and 3 have been established as drivers of numerous types of cancer with multiple drugs approved or entering late stage clinical trials. A limitation of current inhibitors is vulnerability to gatekeeper resistance mutations. Using a combination of targeted high-throughput screening and structure-based drug design, we have developed a series of aminopyrazole based FGFR inhibitors that covalently target a cysteine residue on the P-loop of the kinase. The inhibitors show excellent activity against the wild-type and gatekeeper mutant versions of the enzymes. Further optimization using SAR analysis and structure-based drug design led to analogues with improved potency and drug metabolism and pharmacokinetics properties.
Metabolism of 3-(p-chlorophenyl)pyrrolidine. Structural effects in conversion of a prototype γ-aminobutyric acid prodrug to lactam and γ-aminobutyric acid type metabolites
Wall,Baker
, p. 1340 - 1348 (2007/10/02)
By use of rat liver or brain homogenate supernatants containing microsomes and/or mitochondria, it was found that the prototype GABAergic prodrug [3-(p-chlorophenyl)pyrrolidine (1) underwent a series of α-oxidation transformations to a pair of amino acid metabolites and a pair of lactam metabolites [4-amino-3-(p-chlorophenyl)butanoic acid, baclofen (5); 4-amino-2-(p-chlorophenyl)butanoic acid (10); 4-(chlorophenyl)pyrrolidin-2-one (6); and 3-(p-chlorophenyl)pyrrolidine-2-one (11)]. With the liver homogenates, the formation of the lactam metabolites was approximately 2 orders of magnitude greater than that of the amino acid metabolites, while with the brain homogenates, the amino acid and lactam pathways were of similar magnitude. For either tissue, for both the lactam and the amino acid series, attack at the less sterically hindered 5-position of the pyrrolidine ring was greater than the attack at the 2-position (5>10 and 6>11) with the exception of the liver homogenate mitochondrial fraction (611). The parenteral administration of the prodrug 1 was found to give detectable brain levels of 5 as well as activity in an isoniazid-induced (GABA-inhibited) convulsion model.
