642084-74-0Relevant articles and documents
Design and Synthesis of DDR1 Inhibitors with a Desired Pharmacophore Using Deep Generative Models
Yoshimori, Atsushi,Asawa, Yasunobu,Kawasaki, Enzo,Tasaka, Tomohiko,Matsuda, Seiji,Sekikawa, Toru,Tanabe, Satoshi,Neya, Masahiro,Natsugari, Hideaki,Kanai, Chisato
supporting information, p. 955 - 958 (2021/01/21)
Discoidin domain receptor 1 (DDR1) inhibitors with a desired pharmacophore were designed using deep generative models (DGMs). DDR1 is a receptor tyrosine kinase activated by matrix collagens and implicated in diseases such as cancer, fibrosis and hypoxia. Herein we describe the synthesis and inhibitory activity of compounds generated from DGMs. Three compounds were found to have sub-micromolar inhibitory activity. The most potent of which, compound 3 (N-(4-chloro-3-((pyridin-3-yloxy)methyl)phenyl)-3-(trifluoromethyl)benzamide), had an IC50 value of 92.5 nM. Furthermore, these compounds were predicted to interact with DDR1, which have a desired pharmacophore derived from a known DDR1 inhibitor. The results of synthesis and experiments indicated that our de novo design strategy is practical for hit identification and scaffold hopping.
SUBSTITUTED PYRAZOLO(1,5-A)PYRIMIDINES AND THEIR USE IN THE TREATMENT OF MEDICAL DISORDERS
-
Paragraph 00296, (2016/06/01)
The invention provides substituted pyrazolo[l,5-a]pyrimidine and related organic compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat medical disorders, e.g., Gaucher disease, Parkinson's disease, Lewy body disease, dementia, or multiple system atrophy, in a patient. Exemplary substituted pyrazolo[l,5-a]pyrimidine compounds described herein include 5,7- dimethyl-N-phenylpyrazolo[l,5-a]pyrimidine-3-carboxamide compounds and variants thereof.
Identification of novel p38α MAP kinase inhibitors using fragment-based lead generation
Gill, Adrian L.,Frederickson, Martyn,Cleasby, Anne,Woodhead, Steven J.,Carr, Maria G.,Woodhead, Andrew J.,Walker, Margaret T.,Congreve, Miles S.,Devine, Lindsay A.,Tisi, Dominic,O'Reilly, Marc,Seavers, Lisa C. A.,Davis, Deborah J.,Curry, Jayne,Anthony, Eachel,Padova, Alessandro,Murray, Christopher W.,Carr, Robin A. E.,Jhoti, Harren
, p. 414 - 426 (2007/10/03)
We describe the structure-guided optimization of the molecular fragments 2-amino-3-benzyl-oxypyridine 1 (IC50 1.3 mM) and 3-(2-(4-pyridyl) ethyl)indole 2 (IC50 35 μM) identified using X-ray crystallographic screening of p38α MAP kinase. Using two separate case studies, the article focuses on the key compounds synthesized, the structure-activity relationships and the binding mode observations made during this optimization process, resulting in two potent lead series that demonstrate significant increases in activity. We describe the process of compound elaboration either through the growing out from fragments into adjacent pockets or through the conjoining of overlapping fragments and demonstrate that we have exploited the mobile conserved activation loop, consisting in part of Asp168-Phe169-Gly170 (DFG), to generate significant improvements in potency and kinase selectivity.
