1393882-35-3Relevant academic research and scientific papers
Structural optimization of pyrazolo[1,5-a]pyrimidine derivatives as potent and highly selective DPP-4 inhibitors
Shen, Jian,Deng, Xinxian,Sun, Ran,Tavallaie, Mojdeh S.,Wang, Juntao,Cai, Qingqing,Lam, Celine,Lei, Shuwen,Fu, Lei,Jiang, Faqin
, (2020/10/02)
Our previous discovery of pyrazolo [1,5-a]pyrimidin-7(4H)-one scaffold-based DPP-4 inhibitors yielded two potent compounds b2 (IC50 = 79 nM) and d1 (IC50 = 49 nM) but characterized by cytotoxicity. Herein, with scaffold hopping and fragment-based drug design strategies, highly potent and selective pyrazolo [1,5-a]pyrimidine DPP-4 inhibitors were found featured by reduced or diminished cytotoxicity. Specifically, c24 (IC50 = 2 nM) exhibits a 25 to 40-fold increase of inhibitory activity respect to those of b2 and d1, respectively, 2-fold from Alogliptin (IC50 = 4 nM), and remarkable selectivity over DPP-8 and DPP-9 (>2000 fold). Further docking studies confirmed that the pyrazolo [1,5-a]pyrimidine core interacts with the S1 pocket whereas its substituted aromatic ring interacts with the sub-S1 pocket. The interactive mode in this case resembles that of Alogliptin and Trelagliptin. Further in vivo IPGTT assays in diabetic mice demonstrated that c24 effectively reduces glucose excursion by 48% at the dose of 10 mg/kg, suggesting that c24 is worthy of further development as a potent anti-diabetes agent.
Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2) as an antiinflammatory target: Discovery and in vivo activity of selective pyrazolo[1,5- a ]pyrimidine inhibitors using a focused library and structure-based optimization approach
Kosugi, Tomomi,Mitchell, Dale R.,Fujino, Aiko,Imai, Minoru,Kambe, Mika,Kobayashi, Shinji,Makino, Hiroaki,Matsueda, Yohei,Oue, Yasuhiro,Komatsu, Kanji,Imaizumi, Keiichiro,Sakai, Yuri,Sugiura, Satoshi,Takenouchi, Osami,Unoki, Gen,Yamakoshi, Yuko,Cunliffe, Vicky,Frearson, Julie,Gordon, Richard,John Harris,Kalloo-Hosein, Heidi,Le, Joelle,Patel, Gita,Simpson, Donald J.,Sherborne, Brad,Thomas, Peter S.,Suzuki, Naotaka,Takimoto-Kamimura, Midori,Kataoka, Ken-Ichiro
supporting information; experimental part, p. 6700 - 6715 (2012/09/25)
A novel class of mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2) inhibitors was discovered through screening a kinase-focused library. A homology model of MAPKAP-K2 was generated and used to guide the initial SAR studies and to rationalize the observed selectivity over CDK2. An X-ray crystal structure of a compound from the active series bound to crystalline MAPKAP-K2 confirmed the predicted binding mode. This has enabled the discovery of a series of pyrazolo[1,5-a]pyrimidine derivatives showing good in vitro cellular potency as anti-TNF-α agents and in vivo efficacy in a mouse model of endotoxin shock.
