|
Binding affinity to gag polyprotein in wild type HIV1 NLRepRlucP373S infected in human MT2 cells assessed as inhibition of viral maturation after 4 to 5 days in presence of 10% fetal bovine serum by dual-luciferase reporter assay
|
Human immunodeficiency virus 1
|
1.9
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of BMS-955176, a Second Generation HIV-1 Maturation Inhibitor with Broad Spectrum Antiviral Activity.
Year : 2016
Volume : 7
Issue : 6
First Page : 568
Last Page : 572
Authors : Regueiro-Ren A, Liu Z, Chen Y, Sin N, Sit SY, Swidorski JJ, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Beno BR, Huang XS, Rahematpura S, Parker DD, Haskell R, Jenkins S, Santone KS, Cockett MI, Krystal M, Meanwell NA, Hanumegowda U, Dicker IB.
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.
|
Binding affinity to gag polyprotein in wild type HIV1 NLRepRlucP373S infected in human MT2 cells assessed as inhibition of viral maturation after 4 to 5 days in presence of 10% fetal bovine serum/40% human serum/27 mg/ml human serum albumin by dual-luciferase reporter assay
|
Human immunodeficiency virus 1
|
10.2
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of BMS-955176, a Second Generation HIV-1 Maturation Inhibitor with Broad Spectrum Antiviral Activity.
Year : 2016
Volume : 7
Issue : 6
First Page : 568
Last Page : 572
Authors : Regueiro-Ren A, Liu Z, Chen Y, Sin N, Sit SY, Swidorski JJ, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Beno BR, Huang XS, Rahematpura S, Parker DD, Haskell R, Jenkins S, Santone KS, Cockett MI, Krystal M, Meanwell NA, Hanumegowda U, Dicker IB.
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.
|
Binding affinity to gag polyprotein V370A mutant in HIV1 NLRepRlucP373S infected in human MT2 cells assessed as inhibition of viral maturation after 4 to 5 days in presence of 10% fetal bovine serum by dual-luciferase reporter assay
|
Human immunodeficiency virus 1
|
2.7
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of BMS-955176, a Second Generation HIV-1 Maturation Inhibitor with Broad Spectrum Antiviral Activity.
Year : 2016
Volume : 7
Issue : 6
First Page : 568
Last Page : 572
Authors : Regueiro-Ren A, Liu Z, Chen Y, Sin N, Sit SY, Swidorski JJ, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Beno BR, Huang XS, Rahematpura S, Parker DD, Haskell R, Jenkins S, Santone KS, Cockett MI, Krystal M, Meanwell NA, Hanumegowda U, Dicker IB.
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.
|
Binding affinity to gag polyprotein V370A deletion mutant in HIV1 NLRepRlucP373S infected in human MT2 cells assessed as inhibition of viral maturation after 4 to 5 days in presence of 10% fetal bovine serum by dual-luciferase reporter assay
|
Human immunodeficiency virus 1
|
13.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of BMS-955176, a Second Generation HIV-1 Maturation Inhibitor with Broad Spectrum Antiviral Activity.
Year : 2016
Volume : 7
Issue : 6
First Page : 568
Last Page : 572
Authors : Regueiro-Ren A, Liu Z, Chen Y, Sin N, Sit SY, Swidorski JJ, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Beno BR, Huang XS, Rahematpura S, Parker DD, Haskell R, Jenkins S, Santone KS, Cockett MI, Krystal M, Meanwell NA, Hanumegowda U, Dicker IB.
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.
|
Binding affinity to gag polyprotein V3621 mutant in HIV1 NLRepRlucP373S infected in human MT2 cells assessed as inhibition of viral maturation after 4 to 5 days in presence of 10% fetal bovine serum by dual-luciferase reporter assay
|
Human immunodeficiency virus 1
|
4.5
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of BMS-955176, a Second Generation HIV-1 Maturation Inhibitor with Broad Spectrum Antiviral Activity.
Year : 2016
Volume : 7
Issue : 6
First Page : 568
Last Page : 572
Authors : Regueiro-Ren A, Liu Z, Chen Y, Sin N, Sit SY, Swidorski JJ, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Beno BR, Huang XS, Rahematpura S, Parker DD, Haskell R, Jenkins S, Santone KS, Cockett MI, Krystal M, Meanwell NA, Hanumegowda U, Dicker IB.
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.
|
Binding affinity to gag polyprotein Q369H mutant in HIV1 NLRepRlucP373S infected in human MT2 cells assessed as inhibition of viral maturation after 4 to 5 days in presence of 10% fetal bovine serum by dual-luciferase reporter assay
|
Human immunodeficiency virus 1
|
1.9
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of BMS-955176, a Second Generation HIV-1 Maturation Inhibitor with Broad Spectrum Antiviral Activity.
Year : 2016
Volume : 7
Issue : 6
First Page : 568
Last Page : 572
Authors : Regueiro-Ren A, Liu Z, Chen Y, Sin N, Sit SY, Swidorski JJ, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Beno BR, Huang XS, Rahematpura S, Parker DD, Haskell R, Jenkins S, Santone KS, Cockett MI, Krystal M, Meanwell NA, Hanumegowda U, Dicker IB.
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.
|
Binding affinity to gag polyprotein V370M mutant in HIV1 NLRepRlucP373S infected in human MT2 cells assessed as inhibition of viral maturation after 4 to 5 days in presence of 10% fetal bovine serum by dual-luciferase reporter assay
|
Human immunodeficiency virus 1
|
2.8
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of BMS-955176, a Second Generation HIV-1 Maturation Inhibitor with Broad Spectrum Antiviral Activity.
Year : 2016
Volume : 7
Issue : 6
First Page : 568
Last Page : 572
Authors : Regueiro-Ren A, Liu Z, Chen Y, Sin N, Sit SY, Swidorski JJ, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Beno BR, Huang XS, Rahematpura S, Parker DD, Haskell R, Jenkins S, Santone KS, Cockett MI, Krystal M, Meanwell NA, Hanumegowda U, Dicker IB.
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.
|
Binding affinity to gag polyprotein V370A/T371 deletion mutant in HIV1 NLRepRlucP373S infected in human MT2 cells assessed as inhibition of viral maturation after 4 to 5 days in presence of 10% fetal bovine serum by dual-luciferase reporter assay
|
Human immunodeficiency virus 1
|
3.6
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of BMS-955176, a Second Generation HIV-1 Maturation Inhibitor with Broad Spectrum Antiviral Activity.
Year : 2016
Volume : 7
Issue : 6
First Page : 568
Last Page : 572
Authors : Regueiro-Ren A, Liu Z, Chen Y, Sin N, Sit SY, Swidorski JJ, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Beno BR, Huang XS, Rahematpura S, Parker DD, Haskell R, Jenkins S, Santone KS, Cockett MI, Krystal M, Meanwell NA, Hanumegowda U, Dicker IB.
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.
|
Binding affinity to gag polyprotein V371A deletion mutant in HIV1 NLRepRlucP373S infected in human MT2 cells assessed as inhibition of viral maturation after 4 to 5 days in presence of 10% fetal bovine serum by dual-luciferase reporter assay
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of BMS-955176, a Second Generation HIV-1 Maturation Inhibitor with Broad Spectrum Antiviral Activity.
Year : 2016
Volume : 7
Issue : 6
First Page : 568
Last Page : 572
Authors : Regueiro-Ren A, Liu Z, Chen Y, Sin N, Sit SY, Swidorski JJ, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Beno BR, Huang XS, Rahematpura S, Parker DD, Haskell R, Jenkins S, Santone KS, Cockett MI, Krystal M, Meanwell NA, Hanumegowda U, Dicker IB.
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.
|
Binding affinity to gag polyprotein T371 deletion mutant in HIV1 NLRepRlucP373S infected in human MT2 cells assessed as inhibition of viral maturation after 4 to 5 days in presence of 10% fetal bovine serum by dual-luciferase reporter assay
|
Human immunodeficiency virus 1
|
7.3
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of BMS-955176, a Second Generation HIV-1 Maturation Inhibitor with Broad Spectrum Antiviral Activity.
Year : 2016
Volume : 7
Issue : 6
First Page : 568
Last Page : 572
Authors : Regueiro-Ren A, Liu Z, Chen Y, Sin N, Sit SY, Swidorski JJ, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Beno BR, Huang XS, Rahematpura S, Parker DD, Haskell R, Jenkins S, Santone KS, Cockett MI, Krystal M, Meanwell NA, Hanumegowda U, Dicker IB.
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.
|
Binding affinity to gag polyprotein in HIV1 NLRepRlucP373S infected in human MT2 cells assessed as inhibition of viral maturation
|
Human immunodeficiency virus 1
|
3.9
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of BMS-955176, a Second Generation HIV-1 Maturation Inhibitor with Broad Spectrum Antiviral Activity.
Year : 2016
Volume : 7
Issue : 6
First Page : 568
Last Page : 572
Authors : Regueiro-Ren A, Liu Z, Chen Y, Sin N, Sit SY, Swidorski JJ, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Beno BR, Huang XS, Rahematpura S, Parker DD, Haskell R, Jenkins S, Santone KS, Cockett MI, Krystal M, Meanwell NA, Hanumegowda U, Dicker IB.
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.
|
Antiviral activity against wild type HIV1 infected in human MT2 cells after 4 to 5 days by dual luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
1.9
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176).
Year : 2018
Volume : 61
Issue : 16
First Page : 7289
Last Page : 7313
Authors : Regueiro-Ren A, Swidorski JJ, Liu Z, Chen Y, Sin N, Sit SY, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Easter J, Beno BR, Arora V, Huang XS, Rahematpura S, Parker DD, Haskell R, Santone KS, Cockett MI, Krystal M, Meanwell NA, Jenkins S, Hanumegowda U, Dicker IB.
Abstract : GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC50 <15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.
|
Antiviral activity against HIV1 expressing gag V370A mutant infected in human MT2 cells after 4 to 5 days by dual luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
2.7
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176).
Year : 2018
Volume : 61
Issue : 16
First Page : 7289
Last Page : 7313
Authors : Regueiro-Ren A, Swidorski JJ, Liu Z, Chen Y, Sin N, Sit SY, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Easter J, Beno BR, Arora V, Huang XS, Rahematpura S, Parker DD, Haskell R, Santone KS, Cockett MI, Krystal M, Meanwell NA, Jenkins S, Hanumegowda U, Dicker IB.
Abstract : GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC50 <15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.
|
Antiviral activity against HIV1 expressing gag delta V370 mutant infected in human MT2 cells after 4 to 5 days by dual luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
13.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176).
Year : 2018
Volume : 61
Issue : 16
First Page : 7289
Last Page : 7313
Authors : Regueiro-Ren A, Swidorski JJ, Liu Z, Chen Y, Sin N, Sit SY, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Easter J, Beno BR, Arora V, Huang XS, Rahematpura S, Parker DD, Haskell R, Santone KS, Cockett MI, Krystal M, Meanwell NA, Jenkins S, Hanumegowda U, Dicker IB.
Abstract : GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC50 <15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.
|
Antiviral activity against HIV1 expressing gag V362I mutant infected in human MT2 cells after 4 to 5 days by dual luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
4.5
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176).
Year : 2018
Volume : 61
Issue : 16
First Page : 7289
Last Page : 7313
Authors : Regueiro-Ren A, Swidorski JJ, Liu Z, Chen Y, Sin N, Sit SY, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Easter J, Beno BR, Arora V, Huang XS, Rahematpura S, Parker DD, Haskell R, Santone KS, Cockett MI, Krystal M, Meanwell NA, Jenkins S, Hanumegowda U, Dicker IB.
Abstract : GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC50 <15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.
|
Antiviral activity against HIV1 expressing gag Q369H mutant infected in human MT2 cells after 4 to 5 days by dual luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
1.9
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176).
Year : 2018
Volume : 61
Issue : 16
First Page : 7289
Last Page : 7313
Authors : Regueiro-Ren A, Swidorski JJ, Liu Z, Chen Y, Sin N, Sit SY, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Easter J, Beno BR, Arora V, Huang XS, Rahematpura S, Parker DD, Haskell R, Santone KS, Cockett MI, Krystal M, Meanwell NA, Jenkins S, Hanumegowda U, Dicker IB.
Abstract : GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC50 <15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.
|
Antiviral activity against HIV1 expressing gag V370M mutant infected in human MT2 cells after 4 to 5 days by dual luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
2.8
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176).
Year : 2018
Volume : 61
Issue : 16
First Page : 7289
Last Page : 7313
Authors : Regueiro-Ren A, Swidorski JJ, Liu Z, Chen Y, Sin N, Sit SY, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Easter J, Beno BR, Arora V, Huang XS, Rahematpura S, Parker DD, Haskell R, Santone KS, Cockett MI, Krystal M, Meanwell NA, Jenkins S, Hanumegowda U, Dicker IB.
Abstract : GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC50 <15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.
|
Antiviral activity against HIV1 expressing gag V370A/delta T371 double mutant infected in human MT2 cells after 4 to 5 days by dual luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
3.6
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176).
Year : 2018
Volume : 61
Issue : 16
First Page : 7289
Last Page : 7313
Authors : Regueiro-Ren A, Swidorski JJ, Liu Z, Chen Y, Sin N, Sit SY, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Easter J, Beno BR, Arora V, Huang XS, Rahematpura S, Parker DD, Haskell R, Santone KS, Cockett MI, Krystal M, Meanwell NA, Jenkins S, Hanumegowda U, Dicker IB.
Abstract : GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC50 <15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.
|
Antiviral activity against HIV1 expressing gag T371A mutant infected in human MT2 cells after 4 to 5 days by dual luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176).
Year : 2018
Volume : 61
Issue : 16
First Page : 7289
Last Page : 7313
Authors : Regueiro-Ren A, Swidorski JJ, Liu Z, Chen Y, Sin N, Sit SY, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Easter J, Beno BR, Arora V, Huang XS, Rahematpura S, Parker DD, Haskell R, Santone KS, Cockett MI, Krystal M, Meanwell NA, Jenkins S, Hanumegowda U, Dicker IB.
Abstract : GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC50 <15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.
|
Antiviral activity against HIV1 expressing gag delta V371 mutant infected in human MT2 cells after 4 to 5 days by dual luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
7.3
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176).
Year : 2018
Volume : 61
Issue : 16
First Page : 7289
Last Page : 7313
Authors : Regueiro-Ren A, Swidorski JJ, Liu Z, Chen Y, Sin N, Sit SY, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Easter J, Beno BR, Arora V, Huang XS, Rahematpura S, Parker DD, Haskell R, Santone KS, Cockett MI, Krystal M, Meanwell NA, Jenkins S, Hanumegowda U, Dicker IB.
Abstract : GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC50 <15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.
|
Binding affinity to wild type HIV1 gag polyprotein containing viral like particle
|
Human immunodeficiency virus 1
|
3.2
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176).
Year : 2018
Volume : 61
Issue : 16
First Page : 7289
Last Page : 7313
Authors : Regueiro-Ren A, Swidorski JJ, Liu Z, Chen Y, Sin N, Sit SY, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Easter J, Beno BR, Arora V, Huang XS, Rahematpura S, Parker DD, Haskell R, Santone KS, Cockett MI, Krystal M, Meanwell NA, Jenkins S, Hanumegowda U, Dicker IB.
Abstract : GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC50 <15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.
|
Binding affinity to HIV1 gag polyprotein V362I mutant containing viral like particle
|
Human immunodeficiency virus 1
|
4.3
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176).
Year : 2018
Volume : 61
Issue : 16
First Page : 7289
Last Page : 7313
Authors : Regueiro-Ren A, Swidorski JJ, Liu Z, Chen Y, Sin N, Sit SY, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Easter J, Beno BR, Arora V, Huang XS, Rahematpura S, Parker DD, Haskell R, Santone KS, Cockett MI, Krystal M, Meanwell NA, Jenkins S, Hanumegowda U, Dicker IB.
Abstract : GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC50 <15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.
|
Binding affinity to HIV1 gag polyprotein V370A mutant containing viral like particle
|
Human immunodeficiency virus 1
|
6.5
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176).
Year : 2018
Volume : 61
Issue : 16
First Page : 7289
Last Page : 7313
Authors : Regueiro-Ren A, Swidorski JJ, Liu Z, Chen Y, Sin N, Sit SY, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Easter J, Beno BR, Arora V, Huang XS, Rahematpura S, Parker DD, Haskell R, Santone KS, Cockett MI, Krystal M, Meanwell NA, Jenkins S, Hanumegowda U, Dicker IB.
Abstract : GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC50 <15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.
|
Binding affinity to HIV1 gag polyprotein delta V370 mutant containing viral like particle
|
Human immunodeficiency virus 1
|
33.6
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176).
Year : 2018
Volume : 61
Issue : 16
First Page : 7289
Last Page : 7313
Authors : Regueiro-Ren A, Swidorski JJ, Liu Z, Chen Y, Sin N, Sit SY, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Easter J, Beno BR, Arora V, Huang XS, Rahematpura S, Parker DD, Haskell R, Santone KS, Cockett MI, Krystal M, Meanwell NA, Jenkins S, Hanumegowda U, Dicker IB.
Abstract : GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC50 <15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.
|
Binding affinity to HIV1 gag polyprotein A364V mutant containing viral like particle
|
Human immunodeficiency virus 1
|
98.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176).
Year : 2018
Volume : 61
Issue : 16
First Page : 7289
Last Page : 7313
Authors : Regueiro-Ren A, Swidorski JJ, Liu Z, Chen Y, Sin N, Sit SY, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Easter J, Beno BR, Arora V, Huang XS, Rahematpura S, Parker DD, Haskell R, Santone KS, Cockett MI, Krystal M, Meanwell NA, Jenkins S, Hanumegowda U, Dicker IB.
Abstract : GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC50 <15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.
|
Antiviral activity against wild type HIV1 infected in human MT2 cells after 4 to 5 days in presence of 10% FBS plus 40% human serum albumin plus 27 mg/ml HSA by dual luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
10.2
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176).
Year : 2018
Volume : 61
Issue : 16
First Page : 7289
Last Page : 7313
Authors : Regueiro-Ren A, Swidorski JJ, Liu Z, Chen Y, Sin N, Sit SY, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Easter J, Beno BR, Arora V, Huang XS, Rahematpura S, Parker DD, Haskell R, Santone KS, Cockett MI, Krystal M, Meanwell NA, Jenkins S, Hanumegowda U, Dicker IB.
Abstract : GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC50 <15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.
|
Binding affinity to wild type HIV-1 NL4-3 CA-SP1 cleavage site of Gag-Pol protein assessed as inhibition of HIV-1 maturation
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Second Generation Inhibitors of HIV-1 Maturation.
Year : 2019
Volume : 10
Issue : 3.0
First Page : 287
Last Page : 294
Authors : Regueiro-Ren A,Dicker IB,Hanumegowda U,Meanwell NA
Abstract : The strategy and tactics subtending the discovery and development of the second generation HIV-1 maturation inhibitor GSK-3532795/BMS-955176, a compound that exhibits a broader spectrum of antiviral effect in vitro and in clinical studies than the prototypical maturation inhibitor bevirimat, are described.
|
Binding affinity to HIV-1 CA-SP1 cleavage site of Gag-Pol protein harboring V370A mutant assessed as inhibition of HIV-1 maturation
|
Human immunodeficiency virus 1
|
3.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Second Generation Inhibitors of HIV-1 Maturation.
Year : 2019
Volume : 10
Issue : 3.0
First Page : 287
Last Page : 294
Authors : Regueiro-Ren A,Dicker IB,Hanumegowda U,Meanwell NA
Abstract : The strategy and tactics subtending the discovery and development of the second generation HIV-1 maturation inhibitor GSK-3532795/BMS-955176, a compound that exhibits a broader spectrum of antiviral effect in vitro and in clinical studies than the prototypical maturation inhibitor bevirimat, are described.
|
Binding affinity to wild type HIV-1 NL4-3 CA-SP1 cleavage site of Gag-Pol protein assessed as inhibition of HIV-1 maturation in presence of human serum albumin
|
Human immunodeficiency virus 1
|
10.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Second Generation Inhibitors of HIV-1 Maturation.
Year : 2019
Volume : 10
Issue : 3.0
First Page : 287
Last Page : 294
Authors : Regueiro-Ren A,Dicker IB,Hanumegowda U,Meanwell NA
Abstract : The strategy and tactics subtending the discovery and development of the second generation HIV-1 maturation inhibitor GSK-3532795/BMS-955176, a compound that exhibits a broader spectrum of antiviral effect in vitro and in clinical studies than the prototypical maturation inhibitor bevirimat, are described.
|
Binding affinity to HIV-1 CA-SP1 cleavage site of Gag-pol protein harboring deltaV370 mutant assessed as inhibition of HIV-1 maturation
|
Human immunodeficiency virus 1
|
13.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Second Generation Inhibitors of HIV-1 Maturation.
Year : 2019
Volume : 10
Issue : 3.0
First Page : 287
Last Page : 294
Authors : Regueiro-Ren A,Dicker IB,Hanumegowda U,Meanwell NA
Abstract : The strategy and tactics subtending the discovery and development of the second generation HIV-1 maturation inhibitor GSK-3532795/BMS-955176, a compound that exhibits a broader spectrum of antiviral effect in vitro and in clinical studies than the prototypical maturation inhibitor bevirimat, are described.
|
Binding affinity to HIV-1 CA-SP1 cleavage site of Gag-Pol protein harboring V362I mutant assessed as inhibition of HIV-1 maturation
|
Human immunodeficiency virus 1
|
4.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Second Generation Inhibitors of HIV-1 Maturation.
Year : 2019
Volume : 10
Issue : 3.0
First Page : 287
Last Page : 294
Authors : Regueiro-Ren A,Dicker IB,Hanumegowda U,Meanwell NA
Abstract : The strategy and tactics subtending the discovery and development of the second generation HIV-1 maturation inhibitor GSK-3532795/BMS-955176, a compound that exhibits a broader spectrum of antiviral effect in vitro and in clinical studies than the prototypical maturation inhibitor bevirimat, are described.
|
Binding affinity to HIV-1 CA-SP1 cleavage site of Gag-Pol protein harboring G369H mutant assessed as inhibition of HIV-1 maturation
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Second Generation Inhibitors of HIV-1 Maturation.
Year : 2019
Volume : 10
Issue : 3.0
First Page : 287
Last Page : 294
Authors : Regueiro-Ren A,Dicker IB,Hanumegowda U,Meanwell NA
Abstract : The strategy and tactics subtending the discovery and development of the second generation HIV-1 maturation inhibitor GSK-3532795/BMS-955176, a compound that exhibits a broader spectrum of antiviral effect in vitro and in clinical studies than the prototypical maturation inhibitor bevirimat, are described.
|
Binding affinity to HIV-1 CA-SP1 cleavage site of Gag-Pol protein harboring V370M mutant assessed as inhibition of HIV-1 maturation
|
Human immunodeficiency virus 1
|
3.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Second Generation Inhibitors of HIV-1 Maturation.
Year : 2019
Volume : 10
Issue : 3.0
First Page : 287
Last Page : 294
Authors : Regueiro-Ren A,Dicker IB,Hanumegowda U,Meanwell NA
Abstract : The strategy and tactics subtending the discovery and development of the second generation HIV-1 maturation inhibitor GSK-3532795/BMS-955176, a compound that exhibits a broader spectrum of antiviral effect in vitro and in clinical studies than the prototypical maturation inhibitor bevirimat, are described.
|
Binding affinity to HIV-1 CA-SP1 cleavage site of Gag-Pol protein harboring deltaV370/Thr371Ala mutant assessed as inhibition of HIV-1 maturation
|
Human immunodeficiency virus 1
|
7.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Second Generation Inhibitors of HIV-1 Maturation.
Year : 2019
Volume : 10
Issue : 3.0
First Page : 287
Last Page : 294
Authors : Regueiro-Ren A,Dicker IB,Hanumegowda U,Meanwell NA
Abstract : The strategy and tactics subtending the discovery and development of the second generation HIV-1 maturation inhibitor GSK-3532795/BMS-955176, a compound that exhibits a broader spectrum of antiviral effect in vitro and in clinical studies than the prototypical maturation inhibitor bevirimat, are described.
|
Binding affinity to HIV-1 CA-SP1 cleavage site of Gag-Pol protein harboring Thr371Ala mutant assessed as inhibition of HIV-1 maturation
|
Human immunodeficiency virus 1
|
3.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Second Generation Inhibitors of HIV-1 Maturation.
Year : 2019
Volume : 10
Issue : 3.0
First Page : 287
Last Page : 294
Authors : Regueiro-Ren A,Dicker IB,Hanumegowda U,Meanwell NA
Abstract : The strategy and tactics subtending the discovery and development of the second generation HIV-1 maturation inhibitor GSK-3532795/BMS-955176, a compound that exhibits a broader spectrum of antiviral effect in vitro and in clinical studies than the prototypical maturation inhibitor bevirimat, are described.
|
Binding affinity to HIV-1 CA-SP1 cleavage site of Gag-Pol protein harboring deltaThr371 mutant assessed as inhibition of HIV-1 maturation
|
Human immunodeficiency virus 1
|
5.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Second Generation Inhibitors of HIV-1 Maturation.
Year : 2019
Volume : 10
Issue : 3.0
First Page : 287
Last Page : 294
Authors : Regueiro-Ren A,Dicker IB,Hanumegowda U,Meanwell NA
Abstract : The strategy and tactics subtending the discovery and development of the second generation HIV-1 maturation inhibitor GSK-3532795/BMS-955176, a compound that exhibits a broader spectrum of antiviral effect in vitro and in clinical studies than the prototypical maturation inhibitor bevirimat, are described.
|
Antiviral activity against wild type HIV-1 NL4-3 harbouring Gag AV370 mutant infected in MT-2 cells assessed as inhibition of viral replication in presence of 10% of fetal bovine serum by luciferase reporter gene based multicycle replication assay
|
Human immunodeficiency virus 1
|
13.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design and exploration of C-3 benzoic acid bioisosteres and alkyl replacements in the context of GSK3532795 (BMS-955176) that exhibit broad spectrum HIV-1 maturation inhibition.
Year : 2021
Volume : 36
First Page : 127823
Last Page : 127823
Authors : Swidorski JJ,Jenkins S,Hanumegowda U,Parker DD,Beno BR,Protack T,Ng A,Gupta A,Shanmugam Y,Dicker IB,Krystal M,Meanwell NA,Regueiro-Ren A
Abstract : GSK3532795 (formerly BMS-955176) is a second-generation HIV-1 maturation inhibitor that has shown broad spectrum antiviral activity and preclinical PK predictive of once-daily dosing in humans. Although efficacy was confirmed in clinical trials, the observation of gastrointestinal intolerability and the emergence of drug resistant virus in a Phase 2b clinical study led to the discontinuation of GSK3532795. As part of the effort to further map the maturation inhibitor pharmacophore and provide additional structural options, the evaluation of alternates to the C-3 phenyl substituent in this chemotype was pursued. A cyclohexene carboxylic acid provided exceptional inhibition of wild-type, V370A and ΔV370 mutant viruses in addition to a suitable PK profile following oral dosing to rats. In addition, a novel spiro[3.3]hept-5-ene was designed to extend the carboxylic acid further from the triterpenoid core while reducing side chain flexibility compared to the other alkyl substituents. This modification was shown to closely emulate the C-3 benzoic acid moiety of GSK3532795 from both a potency and PK perspective, providing a non-traditional, sp-rich bioisostere of benzene. Herein, we detail additional modifications to the C-3 position of the triterpenoid core that offer effective replacements for the benzoic acid of GSK3532795 and capture the interplay between these new C-3 elements and C-17 modifications that contribute to enhanced polymorph coverage.
|
Antiviral activity against wild type HIV-1 NL4-3 infected in MT-2 cells assessed as inhibition of viral replication in presence of 10% of fetal bovine serum by luciferase reporter gene based multicycle replication assay
|
Human immunodeficiency virus 1
|
1.8
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design and exploration of C-3 benzoic acid bioisosteres and alkyl replacements in the context of GSK3532795 (BMS-955176) that exhibit broad spectrum HIV-1 maturation inhibition.
Year : 2021
Volume : 36
First Page : 127823
Last Page : 127823
Authors : Swidorski JJ,Jenkins S,Hanumegowda U,Parker DD,Beno BR,Protack T,Ng A,Gupta A,Shanmugam Y,Dicker IB,Krystal M,Meanwell NA,Regueiro-Ren A
Abstract : GSK3532795 (formerly BMS-955176) is a second-generation HIV-1 maturation inhibitor that has shown broad spectrum antiviral activity and preclinical PK predictive of once-daily dosing in humans. Although efficacy was confirmed in clinical trials, the observation of gastrointestinal intolerability and the emergence of drug resistant virus in a Phase 2b clinical study led to the discontinuation of GSK3532795. As part of the effort to further map the maturation inhibitor pharmacophore and provide additional structural options, the evaluation of alternates to the C-3 phenyl substituent in this chemotype was pursued. A cyclohexene carboxylic acid provided exceptional inhibition of wild-type, V370A and ΔV370 mutant viruses in addition to a suitable PK profile following oral dosing to rats. In addition, a novel spiro[3.3]hept-5-ene was designed to extend the carboxylic acid further from the triterpenoid core while reducing side chain flexibility compared to the other alkyl substituents. This modification was shown to closely emulate the C-3 benzoic acid moiety of GSK3532795 from both a potency and PK perspective, providing a non-traditional, sp-rich bioisostere of benzene. Herein, we detail additional modifications to the C-3 position of the triterpenoid core that offer effective replacements for the benzoic acid of GSK3532795 and capture the interplay between these new C-3 elements and C-17 modifications that contribute to enhanced polymorph coverage.
|
Antiviral activity against wild type HIV-1 NL4-3 harbouring Gag V370A mutant infected in MT-2 cells assessed as inhibition of viral replication in presence of 10% of fetal bovine serum by luciferase reporter gene based multicycle replication assay
|
Human immunodeficiency virus 1
|
2.7
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design and exploration of C-3 benzoic acid bioisosteres and alkyl replacements in the context of GSK3532795 (BMS-955176) that exhibit broad spectrum HIV-1 maturation inhibition.
Year : 2021
Volume : 36
First Page : 127823
Last Page : 127823
Authors : Swidorski JJ,Jenkins S,Hanumegowda U,Parker DD,Beno BR,Protack T,Ng A,Gupta A,Shanmugam Y,Dicker IB,Krystal M,Meanwell NA,Regueiro-Ren A
Abstract : GSK3532795 (formerly BMS-955176) is a second-generation HIV-1 maturation inhibitor that has shown broad spectrum antiviral activity and preclinical PK predictive of once-daily dosing in humans. Although efficacy was confirmed in clinical trials, the observation of gastrointestinal intolerability and the emergence of drug resistant virus in a Phase 2b clinical study led to the discontinuation of GSK3532795. As part of the effort to further map the maturation inhibitor pharmacophore and provide additional structural options, the evaluation of alternates to the C-3 phenyl substituent in this chemotype was pursued. A cyclohexene carboxylic acid provided exceptional inhibition of wild-type, V370A and ΔV370 mutant viruses in addition to a suitable PK profile following oral dosing to rats. In addition, a novel spiro[3.3]hept-5-ene was designed to extend the carboxylic acid further from the triterpenoid core while reducing side chain flexibility compared to the other alkyl substituents. This modification was shown to closely emulate the C-3 benzoic acid moiety of GSK3532795 from both a potency and PK perspective, providing a non-traditional, sp-rich bioisostere of benzene. Herein, we detail additional modifications to the C-3 position of the triterpenoid core that offer effective replacements for the benzoic acid of GSK3532795 and capture the interplay between these new C-3 elements and C-17 modifications that contribute to enhanced polymorph coverage.
|
Antiviral activity against wild type HIV-1 NL4-3 harbouring Gag AV370/T371A mutant infected in MT-2 cells assessed as inhibition of viral replication in presence of 10% of fetal bovine serum by luciferase reporter gene based multicycle replication assay
|
Human immunodeficiency virus 1
|
23.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design and exploration of C-3 benzoic acid bioisosteres and alkyl replacements in the context of GSK3532795 (BMS-955176) that exhibit broad spectrum HIV-1 maturation inhibition.
Year : 2021
Volume : 36
First Page : 127823
Last Page : 127823
Authors : Swidorski JJ,Jenkins S,Hanumegowda U,Parker DD,Beno BR,Protack T,Ng A,Gupta A,Shanmugam Y,Dicker IB,Krystal M,Meanwell NA,Regueiro-Ren A
Abstract : GSK3532795 (formerly BMS-955176) is a second-generation HIV-1 maturation inhibitor that has shown broad spectrum antiviral activity and preclinical PK predictive of once-daily dosing in humans. Although efficacy was confirmed in clinical trials, the observation of gastrointestinal intolerability and the emergence of drug resistant virus in a Phase 2b clinical study led to the discontinuation of GSK3532795. As part of the effort to further map the maturation inhibitor pharmacophore and provide additional structural options, the evaluation of alternates to the C-3 phenyl substituent in this chemotype was pursued. A cyclohexene carboxylic acid provided exceptional inhibition of wild-type, V370A and ΔV370 mutant viruses in addition to a suitable PK profile following oral dosing to rats. In addition, a novel spiro[3.3]hept-5-ene was designed to extend the carboxylic acid further from the triterpenoid core while reducing side chain flexibility compared to the other alkyl substituents. This modification was shown to closely emulate the C-3 benzoic acid moiety of GSK3532795 from both a potency and PK perspective, providing a non-traditional, sp-rich bioisostere of benzene. Herein, we detail additional modifications to the C-3 position of the triterpenoid core that offer effective replacements for the benzoic acid of GSK3532795 and capture the interplay between these new C-3 elements and C-17 modifications that contribute to enhanced polymorph coverage.
|
Antiviral activity against wild type HIV-1 NL4-3 harbouring Gag V3621/V370A mutant infected in MT-2 cells assessed as inhibition of viral replication in presence of 10% of fetal bovine serum by luciferase reporter gene based multicycle replication assay
|
Human immunodeficiency virus 1
|
148.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design and exploration of C-3 benzoic acid bioisosteres and alkyl replacements in the context of GSK3532795 (BMS-955176) that exhibit broad spectrum HIV-1 maturation inhibition.
Year : 2021
Volume : 36
First Page : 127823
Last Page : 127823
Authors : Swidorski JJ,Jenkins S,Hanumegowda U,Parker DD,Beno BR,Protack T,Ng A,Gupta A,Shanmugam Y,Dicker IB,Krystal M,Meanwell NA,Regueiro-Ren A
Abstract : GSK3532795 (formerly BMS-955176) is a second-generation HIV-1 maturation inhibitor that has shown broad spectrum antiviral activity and preclinical PK predictive of once-daily dosing in humans. Although efficacy was confirmed in clinical trials, the observation of gastrointestinal intolerability and the emergence of drug resistant virus in a Phase 2b clinical study led to the discontinuation of GSK3532795. As part of the effort to further map the maturation inhibitor pharmacophore and provide additional structural options, the evaluation of alternates to the C-3 phenyl substituent in this chemotype was pursued. A cyclohexene carboxylic acid provided exceptional inhibition of wild-type, V370A and ΔV370 mutant viruses in addition to a suitable PK profile following oral dosing to rats. In addition, a novel spiro[3.3]hept-5-ene was designed to extend the carboxylic acid further from the triterpenoid core while reducing side chain flexibility compared to the other alkyl substituents. This modification was shown to closely emulate the C-3 benzoic acid moiety of GSK3532795 from both a potency and PK perspective, providing a non-traditional, sp-rich bioisostere of benzene. Herein, we detail additional modifications to the C-3 position of the triterpenoid core that offer effective replacements for the benzoic acid of GSK3532795 and capture the interplay between these new C-3 elements and C-17 modifications that contribute to enhanced polymorph coverage.
|
Antiviral activity against wild type HIV-1 NL4-3 infected in MT-2 cells assessed as inhibition of viral replication in presence of 40% human serum and 27 mg/ml human serum albumin by luciferase reporter gene based multicycle replication assay
|
Human immunodeficiency virus 1
|
11.5
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design and exploration of C-3 benzoic acid bioisosteres and alkyl replacements in the context of GSK3532795 (BMS-955176) that exhibit broad spectrum HIV-1 maturation inhibition.
Year : 2021
Volume : 36
First Page : 127823
Last Page : 127823
Authors : Swidorski JJ,Jenkins S,Hanumegowda U,Parker DD,Beno BR,Protack T,Ng A,Gupta A,Shanmugam Y,Dicker IB,Krystal M,Meanwell NA,Regueiro-Ren A
Abstract : GSK3532795 (formerly BMS-955176) is a second-generation HIV-1 maturation inhibitor that has shown broad spectrum antiviral activity and preclinical PK predictive of once-daily dosing in humans. Although efficacy was confirmed in clinical trials, the observation of gastrointestinal intolerability and the emergence of drug resistant virus in a Phase 2b clinical study led to the discontinuation of GSK3532795. As part of the effort to further map the maturation inhibitor pharmacophore and provide additional structural options, the evaluation of alternates to the C-3 phenyl substituent in this chemotype was pursued. A cyclohexene carboxylic acid provided exceptional inhibition of wild-type, V370A and ΔV370 mutant viruses in addition to a suitable PK profile following oral dosing to rats. In addition, a novel spiro[3.3]hept-5-ene was designed to extend the carboxylic acid further from the triterpenoid core while reducing side chain flexibility compared to the other alkyl substituents. This modification was shown to closely emulate the C-3 benzoic acid moiety of GSK3532795 from both a potency and PK perspective, providing a non-traditional, sp-rich bioisostere of benzene. Herein, we detail additional modifications to the C-3 position of the triterpenoid core that offer effective replacements for the benzoic acid of GSK3532795 and capture the interplay between these new C-3 elements and C-17 modifications that contribute to enhanced polymorph coverage.
