Identification and optimization of pyridazinones as potent and selective c-Met kinase inhibitors.
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.
Merck Serono Research & Development, Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany. Electronic address: dieter.dorsch@merckgroup.com.
Dieter
D
Dorsch
Merck Serono Research & Development, Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany.
Oliver
O
Schadt
Merck Serono Research & Development, Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany.
Frank
F
Stieber
Merck Serono Research & Development, Merck KGaA, Am Feld 32, 85567 Grafing, Germany.
Michael
M
Meyring
Merck Serono Research & Development, Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany.
Ulrich
U
Grädler
Merck Serono Research & Development, Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany.
Friedhelm
F
Bladt
Merck Serono Research & Development, Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany.
Manja
M
Friese-Hamim
Merck Serono Research & Development, Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany.
Christine
C
Knühl
Merck Serono Research & Development, Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany.
Ulrich
U
Pehl
Merck Serono Research & Development, Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany.
Andree
A
Blaukat
D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D019859:Proto-Oncogene Proteins c-met
MSC2156119; Pyridazinone; Structure-based design; Tyrosine kinase; c-Met