title: Preclinical stereoselective disposition and toxicokinetics of two novel MET inhibitors.
abstract: The R- and S-enantiomer of N-(4-(3-(1-ethyl-3,3-difluoropiperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide are novel MET kinase inhibitors that have been investigated as potential anticancer agents. The effect of the chirality of these compounds on preclinical in vivo pharmacokinetics and toxicity was studied. The plasma clearance for the S-enantiomer was low in mice and monkeys (23.7 and 7.8 mL min(-1) kg(-1), respectively) and high in rats (79.2 mL min(-1) kg(-1)). The R/S enantiomer clearance ratio was 1.5 except in rats (0.49). After oral single-dose administration at 5 mg kg(-1) the R/S enantiomer ratio of AUC(inf) was 0.95, 1.9 and 0.41 in mice, rats and monkeys, respectively. In an oral single-dose dose-ranging study at 200 and 500 mg kg(-1) and multi-dose toxicity study in mice plasma AUC exposure was approximately 2- to 3-fold higher for the R-enantiomer compared to the S-enantiomer. Greater toxicity of the S-enantiomer was observed which appeared to be due to high plasma C(min) values and tissue concentrations approximately 24 h after the final dose. Both enantiomers showed low to moderate permeability in MDCKI cells with no significant efflux, no preferential distribution into red blood cells and similar plasma protein binding in vitro. Overall, the differences between the enantiomers with respect to low dose pharmacokinetics and in vitro properties were relatively modest. However, toxicity results warrant further development of the R-enantiomer over the S-enantiomer.
authors: Genentech Inc., Drug Metabolism and Pharmacokinetics, South San Francisco, CA 94080, USA. liederer.bianca@gene.com
authors: Bianca M
authors: BM
authors: Liederer
authors: Xingrong
authors: X
authors: Liu
authors: Leonid M
authors: LM
authors: Berezhkovskiy
authors: Gary
authors: G
authors: Cain
authors: Xiao
authors: X
authors: Ding
authors: John
authors: J
authors: Gaudino
authors: Robert
authors: R
authors: Kaus
authors: Emile G
authors: EG
authors: Plise
authors: Daniel P
authors: DP
authors: Sutherlin
authors: Eric B
authors: EB
authors: Harstad
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D001835:Body Weight; D002460:Cell Line; D002463:Cell Membrane Permeability; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D011724:Pyridazines / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013997:Time Factors
chemical_list: D001798:Blood Proteins; C558221:N-(4-(3-(1-ethyl-3-fluoropiperidine-4-ylamino)-1H-pyrazolo(3,4-b)pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011724:Pyridazines; D019859:Proto-Oncogene Proteins c-met