Aware Valmik, Gaikwad Nitin, Chavan Sambhaji, Manohar Sonal, Bose Julie, Khanna Smriti, B-Rao Chandrika, Dixit Neeta, Singh Kishori Sharan, Damre Anagha, Sharma Rajiv, Patil Sambhaji, Roychowdhury Abhijit
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.
Department of Medicinal Chemistry, Piramal Enterprises Limited, Goregaon (East), Mumbai 63, India.
Eur J Med Chem. 2015 Mar 6;92:246-56. doi: 10.1016/j.ejmech.2014.12.053. Epub 2014 Dec 31.
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.
一系列新型的2-氨基-4-吡唑环戊基嘧啶已被制备并作为IGF-1R酪氨酸激酶抑制剂进行评估。发现体外活性强烈依赖于2-氨基环、4-吡唑部分的取代模式以及与中心嘧啶核心稠合的饱和环的大小。通过活性片段组合进行逐步优化，发现了化合物6f和6k，这两种结构的IGF-1R IC50分别为20 nM和10 nM。对6f进一步进行了跨各种细胞系的抗癌活性分析以及在Sprague Dawley大鼠中的药代动力学研究。
