2. Academic Validation
  3. Identification and optimization of pyridazinones as potent and selective c-Met kinase inhibitors

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

  • Bioorg Med Chem Lett. 2015 Apr 1;25(7):1597-602. doi: 10.1016/j.bmcl.2015.02.002.
Dieter Dorsch 1,  Oliver Schadt 2,  Frank Stieber 2,  Michael Meyring 3,  Ulrich Grädler 2,  Friedhelm Bladt 2,  Manja Friese-Hamim 2,  Christine Knühl 2,  Ulrich Pehl 2,  Andree Blaukat 2
Affiliations

Affiliations

  • 1 Merck Serono Research & Development, Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany. Electronic address: dieter.dorsch@merckgroup.com.
  • 2 Merck Serono Research & Development, Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany.
  • 3 Merck Serono Research & Development, Merck KGaA, Am Feld 32, 85567 Grafing, Germany.
PMID: 25736998 DOI: 10.1016/j.bmcl.2015.02.002
Abstract

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.

Keywords

MSC2156119; Pyridazinone; Structure-based design; Tyrosine kinase; c-Met.

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