Discovery of (R)-6-(1-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (AMG 337), a Potent and Selective Inhibitor of MET with High Unbound Target Coverage and Robust In Vivo Antitumor Activity.

Deregulation of the receptor tyrosine kinase mesenchymal epithelial transition factor (MET) has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, we report the discovery of compound 23 (AMG 337), which demonstrates nanomolar inhibition of MET kinase activity, desirable preclinical pharmacokinetics, significant inhibition of MET phosphorylation in mice, and robust tumor growth inhibition in a MET-dependent mouse efficacy model.

Discovery and optimization of potent and selective triazolopyridazine series of c-Met inhibitors.

Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is an attractive target for small molecule drug discovery. We previously showed that O-linked triazolopyridazines can be potent inhibitors of c-Met. Herein, we report the discovery of a related series of N-linked triazolopyridazines which demonstrate nanomolar inhibition of c-Met kinase activity and display improved pharmacodynamic profiles. Specifically, the potent time-dependent inhibition of cytochrome P450 associated with the O-linked triazolopyridazines has been eliminated within this novel series of inhibitors. N-linked triazolopyridazine 24 exhibited favorable pharmacokinetics and displayed potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver PD model. Once-daily oral administration of 24 for 22days showed significant tumor growth inhibition in an NIH-3T3/TPR-Met xenograft mouse efficacy model.

Evaluation of cetirizine hydrochloride-based therapeutic strategy for chronic urticaria.

We investigated the suitability of cetirizine HCl (cetirizine) for the initial treatment of chronic urticaria. A secondary aim was to identify the optimal alternative treatments when switching from this drug to other drugs in patients who are dissatisfied with cetirizine. We started cetirizine at a once-daily dose of 10 mg for 2 weeks and then, depending on the course of symptoms in individual patients, it was either continued, titrated to a higher dose, or switched to other drugs (antihistamines including H2 blockers) for a further 2 weeks. Degrees of patient satisfaction and ratings by physicians were analyzed, as were adverse events. At 2 weeks after the start of treatment, among 74 patients included in the final evaluation 55 (74.3%) expressed satisfaction with cetirizine therapy. Those not satisfied included five (6.7%) who felt drowsy after taking the drug and 14 (18.9%) in whom the drug had not demonstrated adequate efficacy. After optimizing the treatment on a per-patient basis, including switching from cetirizine to other drugs, the percentage satisfied with treatment at 4 weeks was 83.7% (62/74). In the group of patients who were satisfied with the therapy at 2 weeks, attending physicians confirmed that wheals and scratches were significantly alleviated at 2 and 4 weeks, respectively. Adverse effects were mild and uncommon. Cetirizine as an initial treatment for chronic urticaria appears effective and safe. For patients in whom cetirizine fails to satisfactorily alleviate symptoms as well as those who complain of drowsiness, switching to other antihistamine drugs may be an effective strategy.

Discovery and optimization of triazolopyridazines as potent and selective inhibitors of the c-Met kinase.

Tumorigenesis is a multistep process in which oncogenes play a key role in tumor formation, growth, and maintenance. MET was discovered as an oncogene that is activated by its ligand, hepatocyte growth factor. Deregulated signaling in the c-Met pathway has been observed in multiple tumor types. Herein we report the discovery of potent and selective triazolopyridazine small molecules that inhibit c-Met activity.