Imidazole pyrimidine amides as potent, orally bioavailable cyclin-dependent kinase inhibitors.
The development of a novel series of imidazole pyrimidine amides as cyclin-dependent kinase (CDK) inhibitors is described. The series was found to have much improved CDK2 inhibition and potent in vitro anti-proliferative effects against cancer cell lines. Control of overall lipophilicity was important to achieve good in vitro potency along with acceptable physiochemical properties and margins against inhibition of both CYP isoforms and the hERG potassium ion channel. A compound with an attractive overall balance of properties was profiled in vivo and possessed suitable physiochemical and pharmacokinetic profiles for oral dosing.
Jones
Clifford D
CD
Cancer and Infection Research, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. cliff.jones@astrazeneca.com
Andrews
David M
DM
Barker
Andrew J
AJ
Blades
Kevin
K
Byth
Kate F
KF
Finlay
M Raymond V
MR
Geh
Catherine
C
Green
Clive P
CP
Johannsen
Marie
M
Walker
Mike
M
Weir
Hazel M
HM
D000284:Administration, Oral; D000818:Animals; D045744:Cell Line, Tumor; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000138:chemical synthesis* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011743:Pyrimidines / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar
D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D007093:Imidazoles; D011743:Pyrimidines