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Eur J Med Chem. 2015 Mar 6;92:246-56. doi: 10.1016/j.ejmech.2014.12.053. Epub 2014 Dec 31.

Cyclopentyl-pyrimidine based analogues as novel and potent IGF-1R inhibitor.

Author information

1
Department of Medicinal Chemistry, Piramal Enterprises Limited, Goregaon (East), Mumbai 63, India; Organic Chemistry Research Centre, Department of Chemistry, K.R.T. Arts, B.H. Commerce and A.M. Science College, Gangapur Road, Nashik 422 002, MS, India.
2
Department of Medicinal Chemistry, Piramal Enterprises Limited, Goregaon (East), Mumbai 63, India.
3
Molecular Cell Biology and Biochemistry, Piramal Enterprises Limited, Goregaon (East), Mumbai 63, India.
4
Discovery Informatics, Piramal Enterprises Limited, Goregaon (East), Mumbai 63, India.
5
Drug Metabolism and Pharmacokinetics, Piramal Enterprises Limited, Goregaon (East), Mumbai 63, India.
6
Organic Chemistry Research Centre, Department of Chemistry, K.R.T. Arts, B.H. Commerce and A.M. Science College, Gangapur Road, Nashik 422 002, MS, India.
7
Department of Medicinal Chemistry, Piramal Enterprises Limited, Goregaon (East), Mumbai 63, India. Electronic address: abhijitrc@gmail.com.

Abstract

A series of novel 2-amino-4-pyrazolecyclopentylpyrimidines have been prepared and evaluated as IGF-1R tyrosin kinase inhibitors. The in vitro activity was found to depend strongly on the substitution pattern in the 2- amino ring, 4-pyrazolo moieties and size of fused saturated ring with the central pyrimidine core. A stepwise optimization by combination of active fragments led to discovery of compound 6f and 6k, two structures with IGF-1R IC50 of 20 nM and 10 nM, respectively. 6f was further profiled for its anti cancer activity across various cell lines and pharmacokinetic studies in Sprague Dawley rats.

KEYWORDS:

Anti-cancer; Insulin-like growth factor-1 receptor (IGF-IR); Kinase inhibitors; Pyrazoles; Pyrimidines

PMID:
25559205
DOI:
10.1016/j.ejmech.2014.12.053
[Indexed for MEDLINE]

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