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Start Over Author "DENG Hongfeng" Journal journal of medicinal chemistry
6 results on '"DENG Hongfeng"'

1. DNA-Encoded Library Technology-Based Discovery, Lead Optimization, and Prodrug Strategy toward Structurally Unique Indoleamine 2,3-Dioxygenase-1 (IDO1) Inhibitors

Author

Kazmierski, Wieslaw M., primary, Xia, Bing, additional, Miller, John, additional, De la Rosa, Martha, additional, Favre, David, additional, Dunham, Richard M., additional, Washio, Yoshiaki, additional, Zhu, Zhengrong, additional, Wang, Feng, additional, Mebrahtu, Makda, additional, Deng, Hongfeng, additional, Basilla, Jonathan, additional, Wang, Liping, additional, Evindar, Ghotas, additional, Fan, Lijun, additional, Olszewski, Alison, additional, Prabhu, Ninad, additional, Davie, Christopher, additional, Messer, Jeffrey A., additional, and Samano, Vicente, additional

Published
2020
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2. DNA-Encoded Library Technology-Based Discovery, Lead Optimization, and Prodrug Strategy toward Structurally Unique Indoleamine 2,3-Dioxygenase-1 (IDO1) Inhibitors

Author

Kazmierski, Wieslaw M., Xia, Bing, Miller, John, De la Rosa, Martha, Favre, David, Dunham, Richard M., Washio, Yoshiaki, Zhu, Zhengrong, Wang, Feng, Mebrahtu, Makda, Deng, Hongfeng, Basilla, Jonathan, Wang, Liping, Evindar, Ghotas, Fan, Lijun, Olszewski, Alison, Prabhu, Ninad, Davie, Christopher, Messer, Jeffrey A., and Samano, Vicente

Abstract

We report the discovery of a novel indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor class through the affinity selection of a previously unreported indole-based DNA-encoded library (DEL). The DEL exemplar, spiro-chromane 1, had moderate IDO1 potency but high in vivo clearance. Series optimization quickly afforded a potent, low in vivo clearance lead 11. Although amorphous 11was highly bio-available, crystalline 11was poorly soluble and suffered disappointingly low bio-availability because of solubility-limited absorption. A prodrug approach was deployed and proved effective in discovering the highly bio-available phosphonooxymethyl 31, which rapidly converted to 11in vivo. Obtaining crystalline 31proved problematic, however; thus salt screening was performed in an attempt to circumvent this obstacle and successfully delivered greatly soluble and bio-available crystalline tris-salt 32. IDO1 inhibitor 32is characterized by a low calculated human dose, best-in-class potential, and an unusual inhibition mode by binding the IDO1 heme-free (apo) form.

Published
2024
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3. Discovery of Highly Potent and Selective Small Molecule ADAMTS-5 Inhibitors That Inhibit Human Cartilage Degradation via Encoded Library Technology (ELT)

Author

Deng, Hongfeng, primary, O’Keefe, Heather, additional, Davie, Christopher P., additional, Lind, Kenneth E., additional, Acharya, Raksha A., additional, Franklin, G. Joseph, additional, Larkin, Jonathan, additional, Matico, Rosalie, additional, Neeb, Michael, additional, Thompson, Monique M., additional, Lohr, Thomas, additional, Gross, Jeffrey W., additional, Centrella, Paolo A., additional, O’Donovan, Gary K., additional, Bedard, Katie L. (Sargent), additional, van Vloten, Kurt, additional, Mataruse, Sibongile, additional, Skinner, Steven R., additional, Belyanskaya, Svetlana L., additional, Carpenter, Tiffany Y., additional, Shearer, Todd W., additional, Clark, Matthew A., additional, Cuozzo, John W., additional, Arico-Muendel, Christopher C., additional, and Morgan, Barry A., additional

Published
2012
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4. Design, Synthesis, and Biological Evaluation of Peptidomimetic Inhibitors of Factor XIa as Novel Anticoagulants

Author

Lin, Jian, primary, Deng, Hongfeng, additional, Jin, Lei, additional, Pandey, Pramod, additional, Quinn, Jesse, additional, Cantin, Susan, additional, Rynkiewicz, Michael J., additional, Gorga, Joan C., additional, Bibbins, Frank, additional, Celatka, Cassandra A., additional, Nagafuji, Pamela, additional, Bannister, Thomas D., additional, Meyers, Harold V., additional, Babine, Robert E., additional, Hayward, Neil J., additional, Weaver, David, additional, Benjamin, Howard, additional, Stassen, Frans, additional, Abdel-Meguid, Sherin S., additional, and Strickler, James E., additional

Published
2006
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6. Discovery of Highly Potentand Selective Small MoleculeADAMTS-5 Inhibitors That Inhibit Human Cartilage Degradationvia Encoded Library Technology (ELT).

Author

Deng, Hongfeng, O’Keefe, Heather, Davie, Christopher P., Lind, Kenneth E., Acharya, Raksha A., Franklin, G. Joseph, Larkin, Jonathan, Matico, Rosalie, Neeb, Michael, Thompson, Monique M., Lohr, Thomas, Gross, Jeffrey W., Centrella, Paolo A., O’Donovan, Gary K., Bedard, Katie L. (Sargent), van Vloten, Kurt, Mataruse, Sibongile, Skinner, Steven R., Belyanskaya, Svetlana L., and Carpenter, Tiffany Y.

Subjects
*PHARMACEUTICAL research, *DRUG synergism, *ENZYME inhibitors, *METALLOPROTEINASES, *OSTEOARTHRITIS treatment, *DNA, *GLYCOSAMINOGLYCANS
Abstract

The metalloprotease ADAMTS-5 is considered a potentialtarget forthe treatment of osteoarthritis. To identify selective inhibitorsof ADAMTS-5, we employed encoded library technology (ELT), which enablesaffinity selection of small molecule binders from complex mixturesby DNA tagging. Selection of ADAMTS-5 against a four-billion memberELT library led to a novel inhibitor scaffold not containing a classicalzinc-binding functionality. One exemplar, (R)-N-((1-(4-(but-3-en-1-ylamino)-6-(((2-(thiophen-2-yl)thiazol-4-yl)methyl)amino)-1,3,5-triazin-2-yl)pyrrolidin-2-yl)methyl)-4-propylbenzenesulfonamide(8), inhibited ADAMTS-5 with IC50= 30 nM,showing >50-fold selectivity against ADAMTS-4 and >1000-foldselectivityagainst ADAMTS-1, ADAMTS-13, MMP-13, and TACE. Extensive SAR studiesshowed that potency and physicochemical properties of the scaffoldcould be further improved. Furthermore, in a human osteoarthritiscartilage explant study, compounds 8and 15finhibited aggrecanase-mediated 374ARGS neoepitope releasefrom aggrecan and glycosaminoglycan in response to IL-1β/OSMstimulation. This study provides the first small molecule evidencefor the critical role of ADAMTS-5 in human cartilage degradation. [ABSTRACT FROM AUTHOR]

Published
2012
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