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Start Over Author "Xie, Zhiwei" Journal journal of medicinal chemistry
6 results on '"Xie, Zhiwei"'

1. Discovery of Acyl-sulfonamide Nav1.7 Inhibitors GDC-0276 and GDC-0310

Author

Safina, Brian S., primary, McKerrall, Steven J., additional, Sun, Shaoyi, additional, Chen, Chien-An, additional, Chowdhury, Sultan, additional, Jia, Qi, additional, Li, Jun, additional, Zenova, Alla Y., additional, Andrez, Jean-Christophe, additional, Bankar, Girish, additional, Bergeron, Philippe, additional, Chang, Jae H., additional, Chang, Elaine, additional, Chen, Jun, additional, Dean, Richard, additional, Decker, Shannon M., additional, DiPasquale, Antonio, additional, Focken, Thilo, additional, Hemeon, Ivan, additional, Khakh, Kuldip, additional, Kim, Amy, additional, Kwan, Rainbow, additional, Lindgren, Andrea, additional, Lin, Sophia, additional, Maher, Jonathan, additional, Mezeyova, Janette, additional, Misner, Dinah, additional, Nelkenbrecher, Karen, additional, Pang, Jodie, additional, Reese, Rebecca, additional, Shields, Shannon D., additional, Sojo, Luis, additional, Sheng, Tao, additional, Verschoof, Henry, additional, Waldbrook, Matthew, additional, Wilson, Michael S., additional, Xie, Zhiwei, additional, Young, Clint, additional, Zabka, Tanja S., additional, Hackos, David H., additional, Ortwine, Daniel F., additional, White, Andrew D., additional, Johnson, J.P., additional, Robinette, C. Lee, additional, Dehnhardt, Christoph M., additional, Cohen, Charles J., additional, and Sutherlin, Daniel P., additional

Published
2021
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2. Identification of Selective Acyl Sulfonamide–Cycloalkylether Inhibitors of the Voltage-Gated Sodium Channel (NaV) 1.7 with Potent Analgesic Activity

Author

Sun, Shaoyi, primary, Jia, Qi, additional, Zenova, Alla Y., additional, Wilson, Michael S., additional, Chowdhury, Sultan, additional, Focken, Thilo, additional, Li, Jun, additional, Decker, Shannon, additional, Grimwood, Michael E., additional, Andrez, Jean-Christophe, additional, Hemeon, Ivan, additional, Sheng, Tao, additional, Chen, Chien-An, additional, White, Andy, additional, Hackos, David H., additional, Deng, Lunbin, additional, Bankar, Girish, additional, Khakh, Kuldip, additional, Chang, Elaine, additional, Kwan, Rainbow, additional, Lin, Sophia, additional, Nelkenbrecher, Karen, additional, Sellers, Benjamin D., additional, DiPasquale, Antonio G., additional, Chang, Jae, additional, Pang, Jodie, additional, Sojo, Luis, additional, Lindgren, Andrea, additional, Waldbrook, Matthew, additional, Xie, Zhiwei, additional, Young, Clint, additional, Johnson, James P., additional, Robinette, C. Lee, additional, Cohen, Charles J., additional, Safina, Brian S., additional, Sutherlin, Daniel P., additional, Ortwine, Daniel F., additional, and Dehnhardt, Christoph M., additional

Published
2018
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3. Design of Conformationally Constrained Acyl Sulfonamide Isosteres: Identification of N-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)methane-sulfonamides as Potent and Selective hNaV1.7 Inhibitors for the Treatment of Pain

Author

Focken, Thilo, primary, Chowdhury, Sultan, additional, Zenova, Alla, additional, Grimwood, Michael E., additional, Chabot, Christine, additional, Sheng, Tao, additional, Hemeon, Ivan, additional, Decker, Shannon M., additional, Wilson, Michael, additional, Bichler, Paul, additional, Jia, Qi, additional, Sun, Shaoyi, additional, Young, Clint, additional, Lin, Sophia, additional, Goodchild, Samuel J., additional, Shuart, Noah G., additional, Chang, Elaine, additional, Xie, Zhiwei, additional, Li, Bowen, additional, Khakh, Kuldip, additional, Bankar, Girish, additional, Waldbrook, Matthew, additional, Kwan, Rainbow, additional, Nelkenbrecher, Karen, additional, Karimi Tari, Parisa, additional, Chahal, Navjot, additional, Sojo, Luis, additional, Robinette, C. Lee, additional, White, Andrew D., additional, Chen, Chien-An, additional, Zhang, Yi, additional, Pang, Jodie, additional, Chang, Jae H., additional, Hackos, David H., additional, Johnson, J. P., additional, Cohen, Charles J., additional, Ortwine, Daniel F., additional, Sutherlin, Daniel P., additional, Dehnhardt, Christoph M., additional, and Safina, Brian S., additional

Published
2018
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4. Discovery of Acyl-sulfonamide Na v 1.7 Inhibitors GDC-0276 and GDC-0310.

Author

Safina BS, McKerrall SJ, Sun S, Chen CA, Chowdhury S, Jia Q, Li J, Zenova AY, Andrez JC, Bankar G, Bergeron P, Chang JH, Chang E, Chen J, Dean R, Decker SM, DiPasquale A, Focken T, Hemeon I, Khakh K, Kim A, Kwan R, Lindgren A, Lin S, Maher J, Mezeyova J, Misner D, Nelkenbrecher K, Pang J, Reese R, Shields SD, Sojo L, Sheng T, Verschoof H, Waldbrook M, Wilson MS, Xie Z, Young C, Zabka TS, Hackos DH, Ortwine DF, White AD, Johnson JP Jr, Robinette CL, Dehnhardt CM, Cohen CJ, and Sutherlin DP

Subjects
Animals, Azetidines chemistry, Azetidines pharmacokinetics, Benzamides chemistry, Benzamides pharmacokinetics, Cells, Cultured, HEK293 Cells, Humans, Piperidines chemistry, Piperidines pharmacokinetics, Piperidines pharmacology, Rats, Sprague-Dawley, Sulfonamides chemistry, Sulfonamides pharmacokinetics, Voltage-Gated Sodium Channel Blockers chemistry, Voltage-Gated Sodium Channel Blockers pharmacokinetics, Rats, Azetidines pharmacology, Benzamides pharmacology, Drug Discovery, NAV1.7 Voltage-Gated Sodium Channel metabolism, Sulfonamides pharmacology, Voltage-Gated Sodium Channel Blockers pharmacology
Abstract

Na v 1.7 is an extensively investigated target for pain with a strong genetic link in humans, yet in spite of this effort, it remains challenging to identify efficacious, selective, and safe inhibitors. Here, we disclose the discovery and preclinical profile of GDC-0276 ( 1 ) and GDC-0310 ( 2 ), selective Na v 1.7 inhibitors that have completed Phase 1 trials. Our initial search focused on close-in analogues to early compound 3 . This resulted in the discovery of GDC-0276 ( 1 ), which possessed improved metabolic stability and an acceptable overall pharmacokinetics profile. To further derisk the predicted human pharmacokinetics and enable QD dosing, additional optimization of the scaffold was conducted, resulting in the discovery of a novel series of N-benzyl piperidine Na v 1.7 inhibitors. Improvement of the metabolic stability by blocking the labile benzylic position led to the discovery of GDC-0310 ( 2 ), which possesses improved Na v selectivity and pharmacokinetic profile over 1 .

Published
2021
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5. Identification of Selective Acyl Sulfonamide-Cycloalkylether Inhibitors of the Voltage-Gated Sodium Channel (Na V ) 1.7 with Potent Analgesic Activity.

Author

Sun S, Jia Q, Zenova AY, Wilson MS, Chowdhury S, Focken T, Li J, Decker S, Grimwood ME, Andrez JC, Hemeon I, Sheng T, Chen CA, White A, Hackos DH, Deng L, Bankar G, Khakh K, Chang E, Kwan R, Lin S, Nelkenbrecher K, Sellers BD, DiPasquale AG, Chang J, Pang J, Sojo L, Lindgren A, Waldbrook M, Xie Z, Young C, Johnson JP, Robinette CL, Cohen CJ, Safina BS, Sutherlin DP, Ortwine DF, and Dehnhardt CM

Subjects
Analgesics metabolism, Analgesics therapeutic use, Animals, Binding Sites, Drug Design, Half-Life, Humans, Male, Mice, Mice, Transgenic, Microsomes, Liver metabolism, Molecular Docking Simulation, NAV1.7 Voltage-Gated Sodium Channel metabolism, Pain chemically induced, Pain drug therapy, Pain pathology, Protein Structure, Tertiary, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Sulfonamides metabolism, Sulfonamides therapeutic use, Voltage-Gated Sodium Channel Blockers metabolism, Voltage-Gated Sodium Channel Blockers therapeutic use, Analgesics chemistry, NAV1.7 Voltage-Gated Sodium Channel chemistry, Sulfonamides chemistry, Voltage-Gated Sodium Channel Blockers chemistry
Abstract

Herein, we report the discovery and optimization of a series of orally bioavailable acyl sulfonamide Na V 1.7 inhibitors that are selective for Na V 1.7 over Na V 1.5 and highly efficacious in in vivo models of pain and hNa V 1.7 target engagement. An analysis of the physicochemical properties of literature Na V 1.7 inhibitors suggested that acyl sulfonamides with high f sp3 could overcome some of the pharmacokinetic (PK) and efficacy challenges seen with existing series. Parallel library syntheses lead to the identification of analogue 7, which exhibited moderate potency against Na V 1.7 and an acceptable PK profile in rodents, but relatively poor stability in human liver microsomes. Further, design strategy then focused on the optimization of potency against hNa V 1.7 and improvement of human metabolic stability, utilizing induced fit docking in our previously disclosed X-ray cocrystal of the Na V 1.7 voltage sensing domain. These investigations culminated in the discovery of tool compound 33, one of the most potent and efficacious Na V 1.7 inhibitors reported to date.

Published
2019
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6. Design of Conformationally Constrained Acyl Sulfonamide Isosteres: Identification of N-([1,2,4]Triazolo[4,3- a]pyridin-3-yl)methane-sulfonamides as Potent and Selective hNa V 1.7 Inhibitors for the Treatment of Pain.

Author

Focken T, Chowdhury S, Zenova A, Grimwood ME, Chabot C, Sheng T, Hemeon I, Decker SM, Wilson M, Bichler P, Jia Q, Sun S, Young C, Lin S, Goodchild SJ, Shuart NG, Chang E, Xie Z, Li B, Khakh K, Bankar G, Waldbrook M, Kwan R, Nelkenbrecher K, Karimi Tari P, Chahal N, Sojo L, Robinette CL, White AD, Chen CA, Zhang Y, Pang J, Chang JH, Hackos DH, Johnson JP Jr, Cohen CJ, Ortwine DF, Sutherlin DP, Dehnhardt CM, and Safina BS

Subjects
Amino Acid Sequence, Animals, Dogs, Drug Stability, Humans, Kinetics, Mice, Molecular Conformation, Pain metabolism, Rats, Sulfonamides pharmacokinetics, Sulfonamides therapeutic use, Voltage-Gated Sodium Channel Blockers pharmacokinetics, Voltage-Gated Sodium Channel Blockers therapeutic use, Drug Design, NAV1.7 Voltage-Gated Sodium Channel metabolism, Pain drug therapy, Sulfonamides chemistry, Sulfonamides pharmacology, Voltage-Gated Sodium Channel Blockers chemistry, Voltage-Gated Sodium Channel Blockers pharmacology
Abstract

The sodium channel Na V 1.7 has emerged as a promising target for the treatment of pain based on strong genetic validation of its role in nociception. In recent years, a number of aryl and acyl sulfonamides have been reported as potent inhibitors of Na V 1.7, with high selectivity over the cardiac isoform Na V 1.5. Herein, we report on the discovery of a novel series of N-([1,2,4]triazolo[4,3- a]pyridin-3-yl)methanesulfonamides as selective Na V 1.7 inhibitors. Starting with the crystal structure of an acyl sulfonamide, we rationalized that cyclization to form a fused heterocycle would improve physicochemical properties, in particular lipophilicity. Our design strategy focused on optimization of potency for block of Na V 1.7 and human metabolic stability. Lead compounds 10, 13 (GNE-131), and 25 showed excellent potency, good in vitro metabolic stability, and low in vivo clearance in mouse, rat, and dog. Compound 13 also displayed excellent efficacy in a transgenic mouse model of induced pain.

Published
2018
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