Identification and optimization of pyridazinones as potent and selective c-Met kinase inhibitors

作者：Dorsch Dieter^*; Schadt Oliver; Stieber Frank; Meyring Michael; Graedler Ulrich; Bladt Friedhelm; Friese Hamim Manja; Knuehl Christine; Pehl Ulrich; Blaukat Andree

来源：Bioorganic & Medicinal Chemistry Letters, 2015, 25(7): 1597-1602.

DOI：10.1016/j.bmcl.2015.02.002

• c-Met
• Tyrosine kinase
• Pyridazinone
• Structure-based design
• MSC2156119

In a high-throughput screening campaign for c-Met kinase inhibitors, a thiadiazinone derivative with a carbamate group was identified as a potent in vitro inhibitor. Subsequent optimization guided by c-Met-inhibitor X-ray structures furnished new compound classes with excellent in vitro and in vivo profiles. The thiadiazinone ring of the HTS hit was first replaced by a pyridazinone followed by an exchange of the carbamate hinge binder with a 1,5-disubstituted pyrimidine. Finally an optimized compound, 22 (MSC2156119), with excellent in vitro potency, high kinase selectivity, long half-life after oral administration and in vivo anti-tumor efficacy at low doses, was selected as a candidate for clinical development.

• 出版日期2015-4-1