c-Met inhibitor 1

Lesinurad is an inhibitor of URAT1 that promoting renal uric acid excretion [1].URAT1 is a transporter in the kidney that regulates uric acid excretion from the body [2].
In the clinical study, lesinurad potently inhibit URAT1 as well as OAT4, another transporter responsible for the renal resorption of urate. In a study, 21 people with hyperuricemia or gout (sUA >= 8.0 mg/dL) were randomized to lesinurad, open-label allopurinol or placebo. Most of the lesinurad-treated patients had sUA < 6 mg/dL after seven days, which were the same effect to patients receiving allopurinol and better than placebo. Also, Lesinurad showed well tolerated in the study [2]. Compared with probenecid, whose efficacy is reducing patients with renal insufficiency, lesinurad may be effective in patients with mildly impaired renal function [1].
References:
[1]. Crittenden DB, Pillinger MH. New therapies for gout. Annu Rev Med, 2013, 64: 325-337.
[2]. Singh JA. Emerging therapies for gout. Expert Opin Emerg Drugs, 2012, 17(4): 511-518.

Discovery of 1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl] -N-(pyridin-2-ylmethyl)methanesulfonamide (MK-8033): A Specific c-Met/Ron dual kinase inhibitor with preferential affinity for the activated state of c-Met.[Pubmed:23379595]

J Med Chem. 2013 Mar 28;56(6):2294-310.

This report documents the first example of a specific inhibitor of protein kinases with preferential binding to the activated kinase conformation: 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one 11r (MK-8033), a dual c-Met/Ron inhibitor under investigation as a treatment for cancer. The design of 11r was based on the desire to reduce time-dependent inhibition of CYP3A4 (TDI) by members of this structural class. A novel two-step protocol for the synthesis of benzylic sulfonamides was developed to access 11r and analogues. We provide a rationale for the observed selectivity based on X-ray crystallographic evidence and discuss selectivity trends with additional examples. Importantly, 11r provides full inhibition of tumor growth in a c-Met amplified (GTL-16) subcutaneous tumor xenograft model and may have an advantage over inactive form kinase inhibitors due to equal potency against a panel of oncogenic activating mutations of c-Met in contrast to c-Met inhibitors without preferential binding to the active kinase conformation.

Lessons from (S)-6-(1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl )quinoline (PF-04254644), an inhibitor of receptor tyrosine kinase c-Met with high protein kinase selectivity but broad phosphodiesterase family inhibition leading to myocardial degeneration in rats.[Pubmed:23944843]

J Med Chem. 2013 Sep 12;56(17):6651-65.

The hepatocyte growth factor (HGF)/c-Met signaling axis is deregulated in many cancers and plays important roles in tumor invasive growth and metastasis. An exclusively selective c-Met inhibitor (S)-6-(1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl )quinoline (8) was discovered from a highly selective high-throughput screening hit via structure-based drug design and medicinal chemistry lead optimization. Compound 8 had many attractive properties meriting preclinical evaluation. Broad off-target screens identified 8 as a pan-phosphodiesterase (PDE) family inhibitor, which was implicated in a sustained increase in heart rate, increased cardiac output, and decreased contractility indices, as well as myocardial degeneration in in vivo safety evaluations in rats. Compound 8 was terminated as a preclinical candidate because of a narrow therapeutic window in cardio-related safety. The learning from multiparameter lead optimization and strategies to avoid the toxicity attrition at the late stage of drug discovery are discussed.

Discovery of 6-(difluoro(6-(4-fluorophenyl)-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)methyl)q uinoline as a highly potent and selective c-Met inhibitor.[Pubmed:27061987]

Eur J Med Chem. 2016 Jun 30;116:239-251.

c-Met/HGF overexpression has been detected in many human malignancies including tumors which are resistant to anticancer therapy. Disrupting the aberrant c-Met/HGF axis has enjoyed significant progress in both preclinical and clinical antitumor campaign. To eliminate the OCH2-related metabolic deficiency of our previously reported triazolotriazine 2, we synthesized a series of CH2-/CF2-linked triazolotriazines and assessed their c-Met activities, leading to the highly potent compound 23 with IC50 values of 0.24 nM of enzymatic activity in c-Met and 0.85 nM of cellular activity in EBC-1 cancer cell line, as well as with complete tumor regression in EBC-1 xenograft mice model at dose of 25 mg/kg via oral administration. Based on its potent anti-proliferative activities and favorable pharmacokinetic properties, 23 has been selected as a drug candidate for preclinical investigation.

Discovery of (S)-1-(1-(Imidazo[1,2-a]pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2, 3]triazolo[4,5-b]pyrazine (volitinib) as a highly potent and selective mesenchymal-epithelial transition factor (c-Met) inhibitor in clinical development for treatment of cancer.[Pubmed:25148209]

J Med Chem. 2014 Sep 25;57(18):7577-89.

HGF/c-Met signaling has been implicated in human cancers. Herein we describe the invention of a series of novel triazolopyrazine c-Met inhibitors. The structure-activity relationship of these compounds was investigated, leading to the identification of compound 28, which demonstrated favorable pharmacokinetic properties in mice and good antitumor activities in the human glioma xenograft model in athymic nude mice.

c-Met inhibitor 1 is an inhibitor of the c-Met receptor signaling pathway useful for the treatment of cancer including gastric, glioblastoma, and pancreatic cancer.

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