Preclinical stereoselective disposition and toxicokinetics of two novel MET inhibitors

Abstract

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

Keywords::

• MET
• stereoselectivity
• enantiomers
• absorption
• tissue distribution
• pharmacokinetics
• disposition
• toxicity

Acknowledgments

The authors thank the Medicinal Chemistry Groups at Array BioPharma, Inc. and Genentech, Inc., the Safety Assessment Group, especially Trung Nguyen, the In Vivo Studies Group, the Pharmaceutics Group, and the DMPK Group at Genentech, Inc. for their contribution to the generation of the data in this manuscript.

Declaration of interest

The authors are employees of Array BioPharma, Inc. or Genentech, Inc. and are alone responsible for the content and writing of this manuscript.