ABSTRACT
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.
Subject(s)
Cyclin-Dependent Kinase Inhibitor Proteins/chemical synthesis , Imidazoles/chemistry , Pyrimidines/chemistry , Administration, Oral , Animals , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor Proteins/pharmacology , Drug Screening Assays, Antitumor , Female , Humans , Inhibitory Concentration 50 , Male , Mice , Mice, Nude , Rats , Rats, WistarABSTRACT
The development of a novel series of imidazole pyrimidine amides as cyclin-dependent kinase (CDK) inhibitors is described. Optimisation of inhibitory potency against multiple CDK's (1, 2 and 9) resulted in imidazole pyrimidine amides with potent in vitro anti-proliferative effects against a range of cancer cell lines. Excellent physiochemical properties and large margins against inhibition of CYP isoforms and the hERG ion channel were achieved by modification of lipophilicity and amine basicity. A candidate with disease model activity in human cancer cell line xenografts and with suitable physiochemical and pharmacokinetic profiles for intravenous (i.v.) dosing was selected for further development as AZD5597.
Subject(s)
Amides/chemistry , Cyclin-Dependent Kinase Inhibitor Proteins/chemistry , Imidazoles/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Pyrimidines/chemistry , Cell Line, Tumor , Chemistry, Physical/methods , Crystallography, X-Ray , Cyclin-Dependent Kinase Inhibitor Proteins/pharmacology , Drug Design , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Imidazoles/pharmacology , Infusions, Intravenous , Models, Chemical , Molecular Conformation , Neoplasm Transplantation , Protein Isoforms , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacologyABSTRACT
A piperazine series of cyclin-dependent kinase (CDK) inhibitors have been identified. The compounds exhibit excellent physiochemical properties and a novel binding mode, whereby a bridging interaction via a water molecule with Asp 86 of CDK2, leads to selectivity for the CDK family of enzymes over other kinases. Piperazines 2e and 2i were subsequently shown to inhibit tumour growth when dosed orally in a nude mouse xenograft study. Additional chemical series that exploit this unexpected interaction with Asp 86 are also described.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cyclin-Dependent Kinases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Piperazines/chemical synthesis , Piperazines/pharmacology , Animals , Antineoplastic Agents/chemistry , Aspartic Acid/chemistry , Aspartic Acid/genetics , Binding Sites , Combinatorial Chemistry Techniques , Cyclin-Dependent Kinase 2/metabolism , Drug Design , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Imidazoles/chemistry , Mice , Mice, Nude , Molecular Structure , Piperazines/chemistry , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
The epidermal growth factor receptor (EGFR) is a promising target for anticancer therapy because of its role in tumor growth, metastasis and angiogenesis, and tumor resistance to chemotherapy and radiotherapy. We have developed a low-molecular-weight EGFR tyrosine kinase inhibitor (EGFR-TKI), ZD1839 (Iressa(2) ). ZD1839, a substituted anilinoquinazoline, is a potent EGFR-TKI (IC(50) = 0.033 micro M) that selectively inhibits EGF-stimulated tumor cell growth (IC(50) = 0.054 micro M) and that blocks EGF-stimulated EGFR autophosphorylation in tumor cells. In studies with mice bearing a range of human tumor-derived xenografts, ZD1839 given p.o. once a day inhibited tumor growth in a dose-dependent manner. The level of expression of EGFR did not determine xenograft tumor sensitivity to ZD1839. Long-term ZD1839 (>3 months) treatment of mice bearing A431 xenografts was well tolerated, and ZD1839 completely inhibited tumor growth and induced regression of established tumors. No drug-resistant tumors appeared during ZD1839 treatment, but some tumors regrew after drug withdrawal. These studies indicate the potential utility of ZD1839 in the treatment of many human tumors and indicate that continuous once-a-day p.o. dosing might be a suitable therapeutic regimen.
