- Design and Synthesis of DDR1 Inhibitors with a Desired Pharmacophore Using Deep Generative Models
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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.
- Yoshimori, Atsushi,Asawa, Yasunobu,Kawasaki, Enzo,Tasaka, Tomohiko,Matsuda, Seiji,Sekikawa, Toru,Tanabe, Satoshi,Neya, Masahiro,Natsugari, Hideaki,Kanai, Chisato
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supporting information
p. 955 - 958
(2021/01/21)
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- SUBSTITUTED PYRROLO[1,2-A]PYRIMIDINES AND THEIR USE IN THE TREATMENT OF MEDICAL DISORDERS
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The invention provides substituted pyrrolo[l,2-a]pyrimi dines 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 pyrrolo[1,2-a]pyrimidines compounds described herein include substituted 2,4-dimethyl-N-phenylpyrrolo[l,2-a]pyrimidine-8-carboxamide compounds and variants thereof.
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- SUBSTITUTED IMIDAZO[1,5-A]PYRIMIDINES AND THEIR USE IN THE TREATMENT OF MEDICAL DISORDERS
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The invention provides substituted imidazo[1,5-a]pyrimidines 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 imidazo[1,5-a]pyrimidine compounds described herein include substituted 2,4-dimethyl-N-phenylimidazo[1,5-a]pyrimidine-8-carboxamide compounds and variants thereof.
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- SUBSTITUTED PYRAZOLO(1,5-A)PYRIMIDINES AND THEIR USE IN THE TREATMENT OF MEDICAL DISORDERS
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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.
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- Identification of novel p38α MAP kinase inhibitors using fragment-based lead generation
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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.
- 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
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p. 414 - 426
(2007/10/03)
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- 3-`(HETERO) ARYLMETHOXY ! PYRIDINES AND THEIR ANALOGUES AS P38 MAP KINASE INHIBITORS
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Compounds of the formula (I), wherein: -X=Y- is selected from -CR2=CR3- and -CR2=N-; R1 is selected from H, halo, NRR', NHC(=O)R, NHC(=O)NRR', NH2SO2R, and C(=O)NRR'; R2 and R3 (where present) are independently selected from H, optionally substituted C1-7 alkyl, optionally substituted C5-20 aryl, optionally substituted C3-20 heterocyclyl, halo, amino, amido, hydroxy, ether, thio, thioether, acylamido, ureido and sulfonamino; R4 is an optionally substituted C5-20 aryl or C5-20 heteroaryl group; and R5 is selected from R5’, halo, NHR5’, C(=O)NHR5’, OR5’, SR5’, NHC(=O)R5’, NHC(=O)NHR5’, NHS(=O)R5’, wherein R5’ is H or C1-3 alkyl (optionally substituted by halo, NH2, OH, SH) are disclosed for use in therapy and for treating diseases ameliorated by inhibiting p38 MAP kinase.
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Page/Page column 68
(2010/11/30)
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