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19 results on '"Zhu, Huichun"'

6. Design and Synthesis of Novel N-Hydroxy-Dihydronaphthyridinones as Potent and Orally Bioavailable HIV-1 Integrase Inhibitors

Author

Johnson, Ted W., Tanis, Steven P., Butler, Scott L., Dalvie, Deepak, DeLisle, Dorothy M., Dress, Klaus R., Flahive, Erik J., Hu, Qiyue, Kuehler, Jon E., Kuki, Atsuo, Liu, Wen, McClellan, Guy A., Peng, Qinghai, Plewe, Michael B., Richardson, Paul F., Smith, Graham L., Solowiej, Jim, Tran, Khanh T., Wang, Hai, Yu, Xiaoming, Zhang, Junhu, and Zhu, Huichun

Abstract

HIV-1 integrase (IN) is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the synthesis of orally bioavailable azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. Here we disclose the design and synthesis of novel tricyclic N-hydroxy-dihydronaphthyridinones as potent, orally bioavailable HIV-1 integrase inhibitors displaying excellent ligand and lipophilic efficiencies.

Published
2024
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7. Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497)

Author

Kung, Pei-Pei, Bingham, Patrick, Brooun, Alexei, Collins, Michael, Deng, Ya-Li, Dinh, Dac, Fan, Connie, Gajiwala, Ketan S., Grantner, Rita, Gukasyan, Hovhannes J., Hu, Wenyue, Huang, Buwen, Kania, Robert, Kephart, Susan E., Krivacic, Cody, Kumpf, Robert A., Khamphavong, Penney, Kraus, Manfred, Liu, Wei, Maegley, Karen A., Nguyen, Lisa, Ren, Shijian, Richter, Dan, Rollins, Robert A., Sach, Neal, Sharma, Shikhar, Sherrill, John, Spangler, Jillian, Stewart, Albert E., Sutton, Scott, Uryu, Sean, Verhelle, Dominique, Wang, Hui, Wang, Shuiwang, Wythes, Martin, Xin, Shuibo, Yamazaki, Shinji, Zhu, Huichun, Zhu, JinJiang, Zehnder, Luke, and Edwards, Martin

Abstract

A new series of lactam-derived EZH2 inhibitors was designed via ligand-based and physicochemical-property-based strategies to address metabolic stability and thermodynamic solubility issues associated with previous lead compound 1. The new inhibitors incorporated an sp3hybridized carbon atom at the 7-position of the lactam moiety present in lead compound 1as a replacement for a dimethylisoxazole group. This transformation enabled optimization of the physicochemical properties and potency compared to compound 1. Analysis of relationships between calculated log D(clogD) values and in vitro metabolic stability and permeability parameters identified a clogD range that afforded an increased probability of achieving favorable ADME data in a single molecule. Compound 23aexhibited the best overlap of potency and pharmaceutical properties as well as robust tumor growth inhibition in vivo and was therefore advanced as a development candidate (PF-06821497). A crystal structure of 23ain complex with the three-protein PRC2 complex enabled understanding of the key structural features required for optimal binding.

Published
2024
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8. Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497)

Author

Kung, Pei-Pei, primary, Bingham, Patrick, additional, Brooun, Alexei, additional, Collins, Michael, additional, Deng, Ya-Li, additional, Dinh, Dac, additional, Fan, Connie, additional, Gajiwala, Ketan S., additional, Grantner, Rita, additional, Gukasyan, Hovhannes J., additional, Hu, Wenyue, additional, Huang, Buwen, additional, Kania, Robert, additional, Kephart, Susan E., additional, Krivacic, Cody, additional, Kumpf, Robert A., additional, Khamphavong, Penney, additional, Kraus, Manfred, additional, Liu, Wei, additional, Maegley, Karen A., additional, Nguyen, Lisa, additional, Ren, Shijian, additional, Richter, Dan, additional, Rollins, Robert A., additional, Sach, Neal, additional, Sharma, Shikhar, additional, Sherrill, John, additional, Spangler, Jillian, additional, Stewart, Albert E., additional, Sutton, Scott, additional, Uryu, Sean, additional, Verhelle, Dominique, additional, Wang, Hui, additional, Wang, Shuiwang, additional, Wythes, Martin, additional, Xin, Shuibo, additional, Yamazaki, Shinji, additional, Zhu, Huichun, additional, Zhu, JinJiang, additional, Zehnder, Luke, additional, and Edwards, Martin, additional

Published
2017
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9. Azaindole N-methyl hydroxamic acids as HIV-1 integrase inhibitors-II. The impact of physicochemical properties on ADME and PK

Author

Tanis, Steven P., Plewe, Michael B., Johnson, Ted W., Butler, Scott L., Dalvie, Deepak, DeLisle, Dorothy, Dress, Klaus R., Hu, Qiyue, Huang, Buwen, Kuehler, Jon E., Kuki, Atsuo, Liu, Wen, Peng, Qinghai, Smith, Graham L., Solowiej, Jim, Tran, Khanh T., Wang, Hai, Yang, Anle, Yin, Chunfeng, Yu, Xiaoming, Zhang, Junhu, and Zhu, Huichun

Published
2010
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10. Discovery of (10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-ros Oncogene 1 (ROS1) with Preclinical Brain Exposure and Broad-Spectrum Potency against ALK-Resistant Mutations

Author

Johnson, Ted W., primary, Richardson, Paul F., additional, Bailey, Simon, additional, Brooun, Alexei, additional, Burke, Benjamin J., additional, Collins, Michael R., additional, Cui, J. Jean, additional, Deal, Judith G., additional, Deng, Ya-Li, additional, Dinh, Dac, additional, Engstrom, Lars D., additional, He, Mingying, additional, Hoffman, Jacqui, additional, Hoffman, Robert L., additional, Huang, Qinhua, additional, Kania, Robert S., additional, Kath, John C., additional, Lam, Hieu, additional, Lam, Justine L., additional, Le, Phuong T., additional, Lingardo, Laura, additional, Liu, Wei, additional, McTigue, Michele, additional, Palmer, Cynthia L., additional, Sach, Neal W., additional, Smeal, Tod, additional, Smith, Graham L., additional, Stewart, Albert E., additional, Timofeevski, Sergei, additional, Zhu, Huichun, additional, Zhu, Jinjiang, additional, Zou, Helen Y., additional, and Edwards, Martin P., additional

Published
2014
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11. Design of Potent and Selective Inhibitors to Overcome Clinical Anaplastic Lymphoma Kinase Mutations Resistant to Crizotinib

Author

Huang, Qinhua, primary, Johnson, Ted W., additional, Bailey, Simon, additional, Brooun, Alexei, additional, Bunker, Kevin D., additional, Burke, Benjamin J., additional, Collins, Michael R., additional, Cook, Andrew S., additional, Cui, J. Jean, additional, Dack, Kevin N., additional, Deal, Judith G., additional, Deng, Ya-Li, additional, Dinh, Dac, additional, Engstrom, Lars D., additional, He, Mingying, additional, Hoffman, Jacqui, additional, Hoffman, Robert L., additional, Johnson, Patrick S., additional, Kania, Robert S., additional, Lam, Hieu, additional, Lam, Justine L., additional, Le, Phuong T., additional, Li, Qiuhua, additional, Lingardo, Laura, additional, Liu, Wei, additional, Lu, Melissa West, additional, McTigue, Michele, additional, Palmer, Cynthia L., additional, Richardson, Paul F., additional, Sach, Neal W., additional, Shen, Hong, additional, Smeal, Tod, additional, Smith, Graham L., additional, Stewart, Albert E., additional, Timofeevski, Sergei, additional, Tsaparikos, Konstantinos, additional, Wang, Hui, additional, Zhu, Huichun, additional, Zhu, Jinjiang, additional, Zou, Helen Y., additional, and Edwards, Martin P., additional

Published
2014
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16. Design and Synthesis of Novel N-Hydroxy-Dihydronaphthyridinones as Potent and Orally Bioavailable HIV-1 Integrase Inhibitors

Author

Johnson, Ted W., primary, Tanis, Steven P., additional, Butler, Scott L., additional, Dalvie, Deepak, additional, DeLisle, Dorothy M., additional, Dress, Klaus R., additional, Flahive, Erik J., additional, Hu, Qiyue, additional, Kuehler, Jon E., additional, Kuki, Atsuo, additional, Liu, Wen, additional, McClellan, Guy A., additional, Peng, Qinghai, additional, Plewe, Michael B., additional, Richardson, Paul F., additional, Smith, Graham L., additional, Solowiej, Jim, additional, Tran, Khanh T., additional, Wang, Hai, additional, Yu, Xiaoming, additional, Zhang, Junhu, additional, and Zhu, Huichun, additional

Published
2011
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18. Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497).

Author

Kung PP, Bingham P, Brooun A, Collins M, Deng YL, Dinh D, Fan C, Gajiwala KS, Grantner R, Gukasyan HJ, Hu W, Huang B, Kania R, Kephart SE, Krivacic C, Kumpf RA, Khamphavong P, Kraus M, Liu W, Maegley KA, Nguyen L, Ren S, Richter D, Rollins RA, Sach N, Sharma S, Sherrill J, Spangler J, Stewart AE, Sutton S, Uryu S, Verhelle D, Wang H, Wang S, Wythes M, Xin S, Yamazaki S, Zhu H, Zhu J, Zehnder L, and Edwards M

Subjects
Administration, Oral, Biological Availability, Cell Line, Tumor, Humans, Isoquinolines administration & dosage, Isoquinolines chemistry, Models, Molecular, Molecular Conformation, Drug Design, Enhancer of Zeste Homolog 2 Protein antagonists & inhibitors, Isoquinolines pharmacokinetics, Isoquinolines pharmacology
Abstract

A new series of lactam-derived EZH2 inhibitors was designed via ligand-based and physicochemical-property-based strategies to address metabolic stability and thermodynamic solubility issues associated with previous lead compound 1. The new inhibitors incorporated an sp 3 hybridized carbon atom at the 7-position of the lactam moiety present in lead compound 1 as a replacement for a dimethylisoxazole group. This transformation enabled optimization of the physicochemical properties and potency compared to compound 1. Analysis of relationships between calculated log D (clogD) values and in vitro metabolic stability and permeability parameters identified a clogD range that afforded an increased probability of achieving favorable ADME data in a single molecule. Compound 23a exhibited the best overlap of potency and pharmaceutical properties as well as robust tumor growth inhibition in vivo and was therefore advanced as a development candidate (PF-06821497). A crystal structure of 23a in complex with the three-protein PRC2 complex enabled understanding of the key structural features required for optimal binding.

Published
2018
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19. (3aS,7aS)-5-[(S)-3,3,3-Trifluoro-2-meth-oxy-2-phenyl-propano-yl]-2,3,4,5,6,7-hexa-hydro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one monohydrate.

Author

Zhu H, Plewe MB, Rheingold AL, Moore C, and Yanovsky A

Abstract

rac-Benzyl 3-oxohexa-hydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxyl-ate was separated by chiral chromatography, and one of the enanti-omers ([α](22) (D) = +10°) was hydrogenated in the presence of Pd/C in methanol, producing octa-hydro-3H-pyrrolo[3,4-c]pyridin-3-one. The latter was reacted with (2R)-3,3,3-trifluoro-2-meth-oxy-2-phenyl-propanoyl chloride [(R)-(-)-Mosher acid chloride], giving rise to the title compound, C(17)H(19)F(3)N(2)O(3)·H(2)O. The present structure established the absolute configuration of the pyrrolopiperidine fragment based on the known configuration of the (R)-Mosher acid chloride. The piperidine ring has a somewhat distorted chair conformation and is cis-fused with the five-membered envelope-shaped ring; the plane of the exocyclic amide bond is approximately orthogonal to the plane of the phenyl ring, making a dihedral angle of 82.31 (3)°. The water mol-ecule acts as an acceptor to the proton of the amino group in an N-H⋯O inter-action, and as a double proton donor in O-H⋯O hydrogen bonds, generating infinite bands along the a axis.

Published
2009
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