Aurora kinase inhibitors based on the imidazo[1,2-a]pyrazine core: fluorine and deuterium incorporation improve oral absorption and exposure.
Aurora kinases are cell cycle regulated serine/threonine kinases that have been linked to cancer. Compound 1 was identified as a potent Aurora inhibitor but lacked oral bioavailability. Optimization of 1 led to the discovery of a series of fluoroamine and deuterated analogues, exemplified by compound 25, with an improved pharmacokinetic profile. We found that blocking oxidative metabolism at the benzylic position and decreasing the basicity of the amine are important to obtaining compounds with good biological profiles and oral bioavailability.
Department of Chemical Research, Merck Research Laboratories, Kenilworth, New Jersey 07033, United States. angela.kerekes@merck.com
Angela D
AD
Kerekes
Sara J
SJ
Esposite
Ronald J
RJ
Doll
Jayaram R
JR
Tagat
Tao
T
Yu
Yushi
Y
Xiao
Yonglian
Y
Zhang
Dan B
DB
Prelusky
Seema
S
Tevar
Kimberly
K
Gray
Gaby A
GA
Terracina
Suining
S
Lee
Jennifer
J
Jones
Ming
M
Liu
Andrea D
AD
Basso
Elizabeth B
EB
Smith
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D064127:Aurora Kinases; D001682:Biological Availability; D045744:Cell Line, Tumor; D003903:Deuterium; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D005461:Fluorine; D006657:Histones / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008252:Macaca fascicularis; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D006657:Histones; D007093:Imidazoles; D011719:Pyrazines; D005461:Fluorine; D003903:Deuterium; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases