Discovery and Pharmacokinetic and Pharmacological Properties of the Potent and Selective MET Kinase Inhibitor 1-{6-[6-(4-Fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl]benzothiazol-2-yl}-3-(2-morpholin-4-ylethyl)urea (SAR125844)

Abstract

The HGF/MET pathway is frequently activated in a variety of cancer types. Several selective small molecule inhibitors of the MET kinase are currently in clinical evaluation, in particular for NSCLC, liver, and gastric cancer patients. We report herein the discovery of a series of triazolopyridazines that are selective inhibitors of wild-type (WT) MET kinase and several clinically relevant mutants. We provide insight into their mode of binding and report unprecedented crystal structures of the Y1230H variant. A multiparametric chemical optimization approach allowed the identification of compound 12 (SAR125844) as a development candidate. In this chemical series, absence of CYP3A4 inhibition was obtained at the expense of satisfactory oral absorption. Compound 12, a promising parenteral agent for the treatment of MET-dependent cancers, promoted sustained target engagement at tolerated doses in a human xenograft tumor model. Preclinical pharmacokinetics conducted in several species were predictive for the observed pharmacokinetic behavior of 12 in cancer patients.

Molecular design opportunities presented by solvent‐exposed regions of target proteins

“…The privileged structure is a very important concept in medicinal chemistry . Interestingly, some privileged (solvent‐friendly) moieties, including sulfonyl, sulfonamide, morpholine, piperidine, and piperazine, have been introduced into solvent‐exposed regions to improve aqueous solubility, cellular permeability, and metabolic stability . In addition, clusters are novel and potentially useful privileged moieties for the inhibition of certain enzymes, since they can fill particularly large, flexible, or open active sites in unique ways …”

Status of Agents Targeting the HGF/c-Met Axis in Lung Cancer

“…Xenograft studies with MET amplified gastric tumor cells showed significant tumor growth inhibition because of antiproliferative and proapoptotic effects of the drug and down regulation of PI3K/AKT and RAS/MAPK pathways [ 42 ]. Pharmacokinetics studies were performed and analyzed in several species from mice to dog [ 43 ]. Phase I dose escalation and dose expansion study in patients with advanced tumors showed modest antitumor response in patients with MET amplified gastric cancers at 570 mg/m 2 and was well tolerated [ 44 ].…”

Simple Synthesis of a Heterocyclophane Exhibiting Anti‐c‐Met Activity by Acting as a Hatch Blocking Access to the Active Site**

“…In the present study, we developed a novel inhibitor of c‐Met [14–16] . In our previous work, we synthesized heterocyclophanes containing azole rings, such as imidazole, [17] oxazole, [18, 19] and bithiazole [20] .…”