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Literature DB >> 27326328

Discovery of BMS-955176, a Second Generation HIV-1 Maturation Inhibitor with Broad Spectrum Antiviral Activity.

Alicia Regueiro-Ren¹, Zheng Liu¹, Yan Chen¹, Ny Sin¹, Sing-Yuen Sit¹, Jacob J Swidorski¹, Jie Chen¹, Brian L Venables¹, Juliang Zhu¹, Beata Nowicka-Sans¹, Tricia Protack¹, Zeyu Lin¹, Brian Terry¹, Himadri Samanta¹, Sharon Zhang¹, Zhufang Li¹, Brett R Beno¹, Xiaohua S Huang¹, Sandhya Rahematpura¹, Dawn D Parker¹, Roy Haskell¹, Susan Jenkins¹, Kenneth S Santone¹, Mark I Cockett¹, Mark Krystal¹, Nicholas A Meanwell¹, Umesh Hanumegowda¹, Ira B Dicker¹.

Abstract

HIV-1 maturation inhibition (MI) has been clinically validated as an approach to the control of HIV-1 infection. However, identifying an MI with both broad polymorphic spectrum coverage and good oral exposure has been challenging. Herein, we describe the design, synthesis, and preclinical characterization of a potent, orally active, second generation HIV-1 MI, BMS-955176 (2), which is currently in Phase IIb clinical trials as part of a combination antiretroviral regimen.

Entities: Disease Species

Keywords: BMS-955176; HIV-1; antiviral; betulinic acid; maturation inhibitors; triterpene

Year: 2016 PMID： 27326328 PMCID： PMC4904268 DOI： 10.1021/acsmedchemlett.6b00010

Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345

16 in total

Review 1. Antiretroviral therapy: current drugs.

Authors: Alice K Pau; Jomy M George
Journal: Infect Dis Clin North Am Date: 2014-09 Impact factor: 5.982

2. Remote modulation of amine basicity by a phenylsulfone and a phenylthio group.

Authors: Rainer E Martin; Baptiste Plancq; Olivier Gavelle; Björn Wagner; Holger Fischer; Stefanie Bendels; Klaus Müller
Journal: ChemMedChem Date: 2007-03 Impact factor: 3.466

Review 3. Drug evaluation: bevirimat--HIV Gag protein and viral maturation inhibitor.

Authors: Zelalem Temesgen; Judith E Feinberg
Journal: Curr Opin Investig Drugs Date: 2006-08

4. Can the further clinical development of bevirimat be justified?

Authors: Mark A Wainberg; Jan Albert
Journal: AIDS Date: 2010-03-13 Impact factor: 4.177

5. Alkyl Amine Bevirimat Derivatives Are Potent and Broadly Active HIV-1 Maturation Inhibitors.

Authors: Emiko Urano; Sherimay D Ablan; Rebecca Mandt; Gary T Pauly; Dina M Sigano; Joel P Schneider; David E Martin; Theodore J Nitz; Carl T Wild; Eric O Freed
Journal: Antimicrob Agents Chemother Date: 2015-10-19 Impact factor: 5.191

6. C-3 benzoic acid derivatives of C-3 deoxybetulinic acid and deoxybetulin as HIV-1 maturation inhibitors.

Authors: Zheng Liu; Jacob J Swidorski; Beata Nowicka-Sans; Brian Terry; Tricia Protack; Zeyu Lin; Himadri Samanta; Sharon Zhang; Zhufang Li; Dawn D Parker; Sandhya Rahematpura; Susan Jenkins; Brett R Beno; Mark Krystal; Nicholas A Meanwell; Ira B Dicker; Alicia Regueiro-Ren
Journal: Bioorg Med Chem Date: 2016-03-02 Impact factor: 3.641

7. Inhibitors of HIV-1 maturation: Development of structure-activity relationship for C-28 amides based on C-3 benzoic acid-modified triterpenoids.

Authors: Jacob J Swidorski; Zheng Liu; Sing-Yuen Sit; Jie Chen; Yan Chen; Ny Sin; Brian L Venables; Dawn D Parker; Beata Nowicka-Sans; Brian J Terry; Tricia Protack; Sandhya Rahematpura; Umesh Hanumegowda; Susan Jenkins; Mark Krystal; Ira B Dicker; Nicholas A Meanwell; Alicia Regueiro-Ren
Journal: Bioorg Med Chem Lett Date: 2016-03-08 Impact factor: 2.823

Review 8. HIV-1 assembly, release and maturation.

Authors: Eric O Freed
Journal: Nat Rev Microbiol Date: 2015-06-29 Impact factor: 60.633

9. New betulinic acid derivatives for bevirimat-resistant human immunodeficiency virus type-1.

Authors: Zhao Dang; Phong Ho; Lei Zhu; Keduo Qian; Kuo-Hsiung Lee; Li Huang; Chin-Ho Chen
Journal: J Med Chem Date: 2013-02-20 Impact factor: 7.446

10. Phase I and II study of the safety, virologic effect, and pharmacokinetics/pharmacodynamics of single-dose 3-o-(3',3'-dimethylsuccinyl)betulinic acid (bevirimat) against human immunodeficiency virus infection.

Authors: Patrick F Smith; Abayomi Ogundele; Alan Forrest; John Wilton; Karl Salzwedel; Judy Doto; Graham P Allaway; David E Martin
Journal: Antimicrob Agents Chemother Date: 2007-07-16 Impact factor: 5.191

13 in total

1. MicroED structures of HIV-1 Gag CTD-SP1 reveal binding interactions with the maturation inhibitor bevirimat.

Authors: Michael D Purdy; Dan Shi; Jakub Chrustowicz; Johan Hattne; Tamir Gonen; Mark Yeager
Journal: Proc Natl Acad Sci U S A Date: 2018-12-10 Impact factor: 11.205

2. Second Generation Inhibitors of HIV-1 Maturation.

Authors: Alicia Regueiro-Ren; Ira B Dicker; Umesh Hanumegowda; Nicholas A Meanwell
Journal: ACS Med Chem Lett Date: 2019-02-08 Impact factor: 4.345

3. Resistance to Second-Generation HIV-1 Maturation Inhibitors.

Authors: Emiko Urano; Uddhav Timilsina; Justin A Kaplan; Sherimay Ablan; Dibya Ghimire; Phuong Pham; Nishani Kuruppu; Rebecca Mandt; Stewart R Durell; Theodore J Nitz; David E Martin; Carl T Wild; Ritu Gaur; Eric O Freed
Journal: J Virol Date: 2019-03-05 Impact factor: 5.103

4. Conserved Interaction of Lentiviral Vif Molecules with HIV-1 Gag and Differential Effects of Species-Specific Vif on Virus Production.

Authors: Wenwen Zheng; Limian Ling; Zhaolong Li; Hong Wang; Yajuan Rui; Wenying Gao; Shaohua Wang; Xing Su; Wei Wei; Xiao-Fang Yu
Journal: J Virol Date: 2017-03-13 Impact factor: 5.103

5. Mechanistic Studies and Modeling Reveal the Origin of Differential Inhibition of Gag Polymorphic Viruses by HIV-1 Maturation Inhibitors.

Authors: Zeyu Lin; Joseph Cantone; Hao Lu; Beata Nowicka-Sans; Tricia Protack; Tian Yuan; Hong Yang; Zheng Liu; Dieter Drexler; Alicia Regueiro-Ren; Nicholas A Meanwell; Mark Cockett; Mark Krystal; Max Lataillade; Ira B Dicker
Journal: PLoS Pathog Date: 2016-11-28 Impact factor: 6.823

6. The Second-Generation Maturation Inhibitor GSK3532795 Maintains Potent Activity Toward HIV Protease Inhibitor-Resistant Clinical Isolates.

Authors: Neelanjana Ray; Tianbo Li; Zeyu Lin; Tricia Protack; Petronella Maria van Ham; Carey Hwang; Mark Krystal; Monique Nijhuis; Max Lataillade; Ira Dicker
Journal: J Acquir Immune Defic Syndr Date: 2017-05-01 Impact factor: 3.731

Discovery of BMS-955176, a Second Generation HIV-1 Maturation Inhibitor with Broad Spectrum Antiviral Activity.

Review 1. Antiretroviral therapy: current drugs.

2. Remote modulation of amine basicity by a phenylsulfone and a phenylthio group.

Review 3. Drug evaluation: bevirimat--HIV Gag protein and viral maturation inhibitor.

4. Can the further clinical development of bevirimat be justified?

5. Alkyl Amine Bevirimat Derivatives Are Potent and Broadly Active HIV-1 Maturation Inhibitors.

6. C-3 benzoic acid derivatives of C-3 deoxybetulinic acid and deoxybetulin as HIV-1 maturation inhibitors.

7. Inhibitors of HIV-1 maturation: Development of structure-activity relationship for C-28 amides based on C-3 benzoic acid-modified triterpenoids.

Review 8. HIV-1 assembly, release and maturation.

9. New betulinic acid derivatives for bevirimat-resistant human immunodeficiency virus type-1.

10. Phase I and II study of the safety, virologic effect, and pharmacokinetics/pharmacodynamics of single-dose 3-o-(3',3'-dimethylsuccinyl)betulinic acid (bevirimat) against human immunodeficiency virus infection.

1. MicroED structures of HIV-1 Gag CTD-SP1 reveal binding interactions with the maturation inhibitor bevirimat.

2. Second Generation Inhibitors of HIV-1 Maturation.

3. Resistance to Second-Generation HIV-1 Maturation Inhibitors.

4. Conserved Interaction of Lentiviral Vif Molecules with HIV-1 Gag and Differential Effects of Species-Specific Vif on Virus Production.

5. Mechanistic Studies and Modeling Reveal the Origin of Differential Inhibition of Gag Polymorphic Viruses by HIV-1 Maturation Inhibitors.

6. The Second-Generation Maturation Inhibitor GSK3532795 Maintains Potent Activity Toward HIV Protease Inhibitor-Resistant Clinical Isolates.

Review 7. Recent Achievements in Medicinal and Supramolecular Chemistry of Betulinic Acid and Its Derivatives ^‡.

Review 8. Anti-retroviral drugs: current state and development in the next decade.

Review 9. Mechanisms underlying of antiretroviral drugs in different cellular reservoirs with a focus on macrophages.

10. Resistance profile of the HIV-1 maturation inhibitor GSK3532795 in vitro and in a clinical study.

Review 1. Antiretroviral therapy: current drugs.

Review 3. Drug evaluation: bevirimat--HIV Gag protein and viral maturation inhibitor.

Review 8. HIV-1 assembly, release and maturation.

Review 7. Recent Achievements in Medicinal and Supramolecular Chemistry of Betulinic Acid and Its Derivatives ‡.

Review 8. Anti-retroviral drugs: current state and development in the next decade.

Review 9. Mechanisms underlying of antiretroviral drugs in different cellular reservoirs with a focus on macrophages.

Review 7. Recent Achievements in Medicinal and Supramolecular Chemistry of Betulinic Acid and Its Derivatives ^‡.