title: Cyclopentyl-pyrimidine based analogues as novel and potent IGF-1R inhibitor.
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.
authors.affiliation: 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.
authors.forename: Valmik
authors.initials: V
authors.lastname: Aware
authors.affiliation: Department of Medicinal Chemistry, Piramal Enterprises Limited, Goregaon (East), Mumbai 63, India.
authors.forename: Nitin
authors.initials: N
authors.lastname: Gaikwad
authors.affiliation: Department of Medicinal Chemistry, Piramal Enterprises Limited, Goregaon (East), Mumbai 63, India.
authors.forename: Sambhaji
authors.initials: S
authors.lastname: Chavan
authors.affiliation: Molecular Cell Biology and Biochemistry, Piramal Enterprises Limited, Goregaon (East), Mumbai 63, India.
authors.forename: Sonal
authors.initials: S
authors.lastname: Manohar
authors.affiliation: Molecular Cell Biology and Biochemistry, Piramal Enterprises Limited, Goregaon (East), Mumbai 63, India.
authors.forename: Julie
authors.initials: J
authors.lastname: Bose
authors.affiliation: Discovery Informatics, Piramal Enterprises Limited, Goregaon (East), Mumbai 63, India.
authors.forename: Smriti
authors.initials: S
authors.lastname: Khanna
authors.affiliation: Discovery Informatics, Piramal Enterprises Limited, Goregaon (East), Mumbai 63, India.
authors.forename: Chandrika
authors.initials: C
authors.lastname: B-Rao
authors.affiliation: Drug Metabolism and Pharmacokinetics, Piramal Enterprises Limited, Goregaon (East), Mumbai 63, India.
authors.forename: Neeta
authors.initials: N
authors.lastname: Dixit
authors.affiliation: Drug Metabolism and Pharmacokinetics, Piramal Enterprises Limited, Goregaon (East), Mumbai 63, India.
authors.forename: Kishori Sharan
authors.initials: KS
authors.lastname: Singh
authors.affiliation: Drug Metabolism and Pharmacokinetics, Piramal Enterprises Limited, Goregaon (East), Mumbai 63, India.
authors.forename: Anagha
authors.initials: A
authors.lastname: Damre
authors.affiliation: Department of Medicinal Chemistry, Piramal Enterprises Limited, Goregaon (East), Mumbai 63, India.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Sharma
authors.affiliation: 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.
authors.forename: Sambhaji
authors.initials: S
authors.lastname: Patil
authors.affiliation: Department of Medicinal Chemistry, Piramal Enterprises Limited, Goregaon (East), Mumbai 63, India. Electronic address: abhijitrc@gmail.com.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Roychowdhury
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003517:Cyclopentanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D003517:Cyclopentanes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D017526:Receptor, IGF Type 1; C030986:pyrimidine
keywords: Anti-cancer; Insulin-like growth factor-1 receptor (IGF-IR); Kinase inhibitors; Pyrazoles; Pyrimidines