Friday, May 29, 2015

Drugs in Clinical Pipeline: AZD5597

AZD5597 [(S)-(4-((5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-yl)amino)phenyl)(3-(methylamino)pyrrolidin-1-yl)methanone] is a potent and selective cyclin-dependent kinase (CDK) inhibitor from a novel series of imidazole pyrimidine amides developed at AstraZeneca. It inhibits both CDK1 and CDK2 with an IC50 value of 0.002 uM, respectively.

The overall profile of AZD5597 indicated that it was suitable for further development as an iv agent. The high margins against hERG allow for flexibility in dosing either as a bolus or by extended infusions. The lack of CYP inhibition lowers the risk of problematic drug–drug interactions in the clinic. Excellent aqueous solubility from crystalline AZD5597 was obtained, even in simple saline formulations. In addition, the formulated drug showed no significant decomposition on exposure to light, plasma or through chemical hydrolysis.

Based on high levels of both enzyme potency and cellular anti-proliferative activity, AZD3147 was selected by AstraZeneca for further development.

Common Name: AZD5597
Synonyms:  AZD-5597; AZD 5597; AZD5597
IUPAC Name: (S)-(4-((5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-yl)amino)phenyl)(3-(methylamino)pyrrolidin-1-yl)methanone
CAS Number: 924641-59-8
Mechanism of Action: Kinase Inhibitor; CDK Inhibitor; CDK2 Inhibitor; CDK1 Inhibitor
Indication: Various Cancers; Anti-tumor Therapy
Development Stage: Investigational
Company: AstraZeneca

Eidogen Sertanty Inc Provides Kinase Knowledge Base (KKB): a Collection of nearly 1.6 M Kinase Inhibitors.

The mammalian target of rapamycin (mTOR), a serine/theronine kinase of approximately 289 kDa in size, is a member of the evolutionary conserved eukaryotic PI3K-related kinase (PIKK) family of atypical protein kinases which also include the protein kinases DNA-PK (DNA dependent protein kinase), ATM (ataxia-telangiectasia mutated) and ATR (ataxiatelangiectasia and Rad3 related). mTOR is a key target in the development of antitumor therapies. Activated by growth factor/mitogenic stimulation activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, mTOR is a central regulator of cell growth and proliferation. This PI3K-Akt-mTOR pathway is one of the most frequently dysregulated pathways in cancer [1].

1. Jones, C. D.; et. al. The discovery of AZD5597, a potent imidazole pyrimidine amide CDK inhibitor suitable for intravenous dosing. Bioorg Med Chem Lett 2008, 18(24), 6369-6373.