|
Inhibition of [3H]dofetilide binding to HERG expressed in HEK293 cells at 300 nM
|
Homo sapiens
|
0.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Overcoming HERG affinity in the discovery of the CCR5 antagonist maraviroc.
Year : 2006
Volume : 16
Issue : 17
First Page : 4633
Last Page : 4637
Authors : Price DA, Armour D, de Groot M, Leishman D, Napier C, Perros M, Stammen BL, Wood A.
Abstract : The discovery of maraviroc 17 is described with particular reference to the generation of high selectivity over affinity for the HERG potassium channel. This was achieved through the use of a high throughput binding assay for the HERG channel that is known to show an excellent correlation with functional effects.
|
Antiviral activity against HIV1 JRCSF by viral entry assay
|
Human immunodeficiency virus 1
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Anti-HIV-1 entry optimization of novel imidazopiperidine-tropane CCR5 antagonists.
Year : 2008
Volume : 18
Issue : 4
First Page : 1498
Last Page : 1501
Authors : Ernst J, Dahl R, Lum C, Sebo L, Urban J, Miller SG, Lundström J.
Abstract : A novel series of imidazopiperidine-tropane CCR5 antagonists is described. The series was optimized for anti-HIV-1 potency using a set of phenotypic viral entry assays. This strategy resulted in the identification of several very potent (IC(50)<10nM) inhibitors of HIV-1 entry. One compound (40) was further profiled and was found to have attractive selectivity, pharmacokinetic, and antiviral properties.
|
Antiviral activity against HIV1 ASM80 by viral entry assay
|
Human immunodeficiency virus 1
|
6.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Anti-HIV-1 entry optimization of novel imidazopiperidine-tropane CCR5 antagonists.
Year : 2008
Volume : 18
Issue : 4
First Page : 1498
Last Page : 1501
Authors : Ernst J, Dahl R, Lum C, Sebo L, Urban J, Miller SG, Lundström J.
Abstract : A novel series of imidazopiperidine-tropane CCR5 antagonists is described. The series was optimized for anti-HIV-1 potency using a set of phenotypic viral entry assays. This strategy resulted in the identification of several very potent (IC(50)<10nM) inhibitors of HIV-1 entry. One compound (40) was further profiled and was found to have attractive selectivity, pharmacokinetic, and antiviral properties.
|
Antiviral activity against HIV1 BaL by viral entry assay
|
Human immunodeficiency virus 1
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Anti-HIV-1 entry optimization of novel imidazopiperidine-tropane CCR5 antagonists.
Year : 2008
Volume : 18
Issue : 4
First Page : 1498
Last Page : 1501
Authors : Ernst J, Dahl R, Lum C, Sebo L, Urban J, Miller SG, Lundström J.
Abstract : A novel series of imidazopiperidine-tropane CCR5 antagonists is described. The series was optimized for anti-HIV-1 potency using a set of phenotypic viral entry assays. This strategy resulted in the identification of several very potent (IC(50)<10nM) inhibitors of HIV-1 entry. One compound (40) was further profiled and was found to have attractive selectivity, pharmacokinetic, and antiviral properties.
|
Antiviral activity against HIV1 97-ZA-003 by viral entry assay
|
Human immunodeficiency virus 1
|
8.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Anti-HIV-1 entry optimization of novel imidazopiperidine-tropane CCR5 antagonists.
Year : 2008
Volume : 18
Issue : 4
First Page : 1498
Last Page : 1501
Authors : Ernst J, Dahl R, Lum C, Sebo L, Urban J, Miller SG, Lundström J.
Abstract : A novel series of imidazopiperidine-tropane CCR5 antagonists is described. The series was optimized for anti-HIV-1 potency using a set of phenotypic viral entry assays. This strategy resulted in the identification of several very potent (IC(50)<10nM) inhibitors of HIV-1 entry. One compound (40) was further profiled and was found to have attractive selectivity, pharmacokinetic, and antiviral properties.
|
Antiviral activity against HIV1 RU570 by viral entry assay
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Anti-HIV-1 entry optimization of novel imidazopiperidine-tropane CCR5 antagonists.
Year : 2008
Volume : 18
Issue : 4
First Page : 1498
Last Page : 1501
Authors : Ernst J, Dahl R, Lum C, Sebo L, Urban J, Miller SG, Lundström J.
Abstract : A novel series of imidazopiperidine-tropane CCR5 antagonists is described. The series was optimized for anti-HIV-1 potency using a set of phenotypic viral entry assays. This strategy resulted in the identification of several very potent (IC(50)<10nM) inhibitors of HIV-1 entry. One compound (40) was further profiled and was found to have attractive selectivity, pharmacokinetic, and antiviral properties.
|
Antagonist activity at human recombinant CCR5 expressed in human HeLa-P4 cells assessed as inhibition of human HeLa-P4 cells binding to HIV1 gp160 expressing CHO cells by cell-cell fusion assay
|
Homo sapiens
|
0.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1-Amido-1-phenyl-3-piperidinylbutanes - CCR5 antagonists for the treatment of HIV. Part 1.
Year : 2009
Volume : 19
Issue : 4
First Page : 1075
Last Page : 1079
Authors : Barber CG, Blakemore DC, Chiva JY, Eastwood RL, Middleton DS, Paradowski KA.
Abstract : The development of a new class of CCR5 antagonist replacing the tropane core of maraviroc by piperidine with a branched N-substituent is described. Compound 15h shows good whole cell antiviral activity together with microsomal stability and only weak activity at the hERG ion channel.
|
Antagonist activity at human recombinant CCR5 expressed in human HeLa-P4 cells assessed as inhibition of human HeLa-P4 cells binding to HIV1 gp160 expressing CHO cells by cell-cell fusion assay
|
Homo sapiens
|
0.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1-Amido-1-phenyl-3-piperidinylbutanes--CCR5 antagonists for the treatment of HIV: part 2.
Year : 2009
Volume : 19
Issue : 5
First Page : 1499
Last Page : 1503
Authors : Barber CG, Blakemore DC, Chiva JY, Eastwood RL, Middleton DS, Paradowski KA.
Abstract : Optimisation of a series of 4-piperidinyltriazoles led to the identification of compound 28a which showed good whole cell antiviral activity, excellent selectivity over the hERG ion channel and complete oral absorption.
|
Inhibition of human ERG channel at 300 uM
|
Homo sapiens
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Side chain flexibilities in the human ether-a-go-go related gene potassium channel (hERG) together with matched-pair binding studies suggest a new binding mode for channel blockers.
Year : 2009
Volume : 52
Issue : 14
First Page : 4266
Last Page : 4276
Authors : Zachariae U, Giordanetto F, Leach AG.
Abstract : The cardiac hERG K(+) channel constitutes a long-standing and expensive antitarget for the drug industry. From a study of the flexibility of hERG around its internal binding cavity, we have developed a new structural model of drug binding to hERG, which involves binding orthogonal to the pore channel and therefore can exploit the up to 4-fold symmetry of the tetrameric channel. This binding site has a base formed by four tyrosine side chains that complement reported ligand-based pharmacophores. The model is able to rationalize reduced hERG potency in matched molecular pair studies and suggests design guidelines to optimize against hERG not relying simply on lipophilicity reduction. The binding model also suggests a molecular mechanism for the link between high-affinity hERG binding and C-type inactivation.
|
Antiviral activity against HIV1 Ba-L infected in HOS cells assessed as inhibition of viral infection
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 4,4-Disubstituted cyclohexylamine based CCR5 chemokine receptor antagonists as anti-HIV-1 agents.
Year : 2009
Volume : 19
Issue : 17
First Page : 4988
Last Page : 4992
Authors : Duan M, Aquino C, Dorsey GF, Ferris R, Kazmierski WM.
Abstract : A series of 4,4-disubstituted cyclohexylamine based CCR5 antagonists has been designed and synthesized. Their antiviral structure-activity relationship has been extensively explored.
|
Displacement of [128I]RANTES from human CCR5 receptor coexpressed with Galphai6 in CHO cells after 2 hrs by scintillation counting
|
Homo sapiens
|
1.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Evaluation of a 3-amino-8-azabicyclo[3.2.1]octane replacement in the CCR5 antagonist maraviroc.
Year : 2010
Volume : 20
Issue : 5
First Page : 1674
Last Page : 1676
Authors : Lemoine RC, Petersen AC, Setti L, Baldinger T, Wanner J, Jekle A, Heilek G, deRosier A, Ji C, Rotstein DM.
Abstract : The bicyclic 5-amino-3-azabicyclo[3.3.0]octanes were shown to be effective replacements for the 3-amino-8-azabicyclo[3.2.1]octane found in the CCR5 antagonist maraviroc.
|
Antiviral activity against CCR5-tropic recombinant HIV1 NLBal virus infected in JC53-BL cells assessed as inhibition of viral replication after 3 days by luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
2.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Evaluation of a 3-amino-8-azabicyclo[3.2.1]octane replacement in the CCR5 antagonist maraviroc.
Year : 2010
Volume : 20
Issue : 5
First Page : 1674
Last Page : 1676
Authors : Lemoine RC, Petersen AC, Setti L, Baldinger T, Wanner J, Jekle A, Heilek G, deRosier A, Ji C, Rotstein DM.
Abstract : The bicyclic 5-amino-3-azabicyclo[3.3.0]octanes were shown to be effective replacements for the 3-amino-8-azabicyclo[3.2.1]octane found in the CCR5 antagonist maraviroc.
|
Binding affinity at CCR5 receptor by radiolabeled RANTES binding assay
|
None
|
14.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel hexahydropyrrolo[3,4-c]pyrrole CCR5 antagonists.
Year : 2010
Volume : 20
Issue : 10
First Page : 3116
Last Page : 3119
Authors : Rotstein DM, Melville CR, Padilla F, Cournoyer D, Lee EK, Lemoine R, Petersen AC, Setti LQ, Wanner J, Chen L, Filonova L, Loughhead DG, Manka J, Lin XF, Gleason S, Sankuratri S, Ji C, Derosier A, Dioszegi M, Heilek G, Jekle A, Berry P, Mau CI, Weller P.
Abstract : Starting with a high-throughput screening lead, a novel series of CCR5 antagonists was developed utilizing an information-based approach. Improvement of pharmacokinetic properties for the series was pursued by SAR exploration of the lead template. The synthesis, SAR and biological profiles of the series are described.
|
Antiviral activity against HIV1 NL4-3 infected in human JC53-BL cells assessed as luciferase activity after 3 days post infection
|
Human immunodeficiency virus 1
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel hexahydropyrrolo[3,4-c]pyrrole CCR5 antagonists.
Year : 2010
Volume : 20
Issue : 10
First Page : 3116
Last Page : 3119
Authors : Rotstein DM, Melville CR, Padilla F, Cournoyer D, Lee EK, Lemoine R, Petersen AC, Setti LQ, Wanner J, Chen L, Filonova L, Loughhead DG, Manka J, Lin XF, Gleason S, Sankuratri S, Ji C, Derosier A, Dioszegi M, Heilek G, Jekle A, Berry P, Mau CI, Weller P.
Abstract : Starting with a high-throughput screening lead, a novel series of CCR5 antagonists was developed utilizing an information-based approach. Improvement of pharmacokinetic properties for the series was pursued by SAR exploration of the lead template. The synthesis, SAR and biological profiles of the series are described.
|
Antiviral activity against HIV1 Ba-L in human PBMC assessed as p24 antigen level by ELISA
|
Human immunodeficiency virus 1
|
3.8
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Long-lasting enfuvirtide carrier pentasaccharide conjugates with potent anti-human immunodeficiency virus type 1 activity.
Year : 2010
Volume : 54
Issue : 1
First Page : 134
Last Page : 142
Authors : Huet T, Kerbarh O, Schols D, Clayette P, Gauchet C, Dubreucq G, Vincent L, Bompais H, Mazinghien R, Querolle O, Salvador A, Lemoine J, Lucidi B, Balzarini J, Petitou M.
Abstract : Enfuvirtide (also known as Fuzeon, T-20, or DP-178) is an antiretroviral fusion inhibitor which prevents human immunodeficiency virus type 1 (HIV-1) from entering host cells. This linear 36-mer synthetic peptide is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1-infected individuals and AIDS patients with multidrug-resistant HIV infections. Although enfuvirtide is an efficient anti-HIV-1 drug, its clinical use is limited by a short plasma half-life, i.e., approximately 2 h, which requires twice-daily subcutaneous injections, often resulting in skin sensitivity reaction side effects at the injection sites. Ultimately, 80% of patients stop enfuvirtide treatment within 6 months because of these side effects. We report on the development of long-lasting enfuvirtide conjugates by the use of the site-specific conjugation of enfuvirtide to an antithrombin-binding carrier pentasaccharide (CP) through polyethylene glycol (PEG) linkers of various lengths. These conjugates showed consistent and broad anti-HIV-1 activity in the nanomolar range. The coupling of the CP to enfuvirtide only moderately affected the in vitro anti-HIV-1 activity in the presence of antithrombin. Most importantly, one of these conjugates, enfuvirtide-PEG(12)-CP (EP40111), exhibited a prolonged elimination half-life of more than 10 h in rat plasma compared to the half-life of native enfuvirtide, which was 2.8 h. On the basis of the pharmacokinetic properties of antithrombin-binding pentasaccharides, the anticipated half-life of EP40111 in humans would putatively be about 120 h, which would allow subcutaneous injection once a week instead of twice daily. In conclusion, EP40111 is a promising compound with strong potency as a novel long-lasting anti-HIV-1 drug.
|
Antiviral activity against HIV1 strain I-2496 in human PBMC assessed as p24 antigen level by ELISA
|
Human immunodeficiency virus 1
|
0.4
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Long-lasting enfuvirtide carrier pentasaccharide conjugates with potent anti-human immunodeficiency virus type 1 activity.
Year : 2010
Volume : 54
Issue : 1
First Page : 134
Last Page : 142
Authors : Huet T, Kerbarh O, Schols D, Clayette P, Gauchet C, Dubreucq G, Vincent L, Bompais H, Mazinghien R, Querolle O, Salvador A, Lemoine J, Lucidi B, Balzarini J, Petitou M.
Abstract : Enfuvirtide (also known as Fuzeon, T-20, or DP-178) is an antiretroviral fusion inhibitor which prevents human immunodeficiency virus type 1 (HIV-1) from entering host cells. This linear 36-mer synthetic peptide is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1-infected individuals and AIDS patients with multidrug-resistant HIV infections. Although enfuvirtide is an efficient anti-HIV-1 drug, its clinical use is limited by a short plasma half-life, i.e., approximately 2 h, which requires twice-daily subcutaneous injections, often resulting in skin sensitivity reaction side effects at the injection sites. Ultimately, 80% of patients stop enfuvirtide treatment within 6 months because of these side effects. We report on the development of long-lasting enfuvirtide conjugates by the use of the site-specific conjugation of enfuvirtide to an antithrombin-binding carrier pentasaccharide (CP) through polyethylene glycol (PEG) linkers of various lengths. These conjugates showed consistent and broad anti-HIV-1 activity in the nanomolar range. The coupling of the CP to enfuvirtide only moderately affected the in vitro anti-HIV-1 activity in the presence of antithrombin. Most importantly, one of these conjugates, enfuvirtide-PEG(12)-CP (EP40111), exhibited a prolonged elimination half-life of more than 10 h in rat plasma compared to the half-life of native enfuvirtide, which was 2.8 h. On the basis of the pharmacokinetic properties of antithrombin-binding pentasaccharides, the anticipated half-life of EP40111 in humans would putatively be about 120 h, which would allow subcutaneous injection once a week instead of twice daily. In conclusion, EP40111 is a promising compound with strong potency as a novel long-lasting anti-HIV-1 drug.
|
Antiviral activity against HIV1 UG273 clade A, R5 in human PBMC assessed as p24 antigen level by ELISA
|
Human immunodeficiency virus 1
|
2.6
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Long-lasting enfuvirtide carrier pentasaccharide conjugates with potent anti-human immunodeficiency virus type 1 activity.
Year : 2010
Volume : 54
Issue : 1
First Page : 134
Last Page : 142
Authors : Huet T, Kerbarh O, Schols D, Clayette P, Gauchet C, Dubreucq G, Vincent L, Bompais H, Mazinghien R, Querolle O, Salvador A, Lemoine J, Lucidi B, Balzarini J, Petitou M.
Abstract : Enfuvirtide (also known as Fuzeon, T-20, or DP-178) is an antiretroviral fusion inhibitor which prevents human immunodeficiency virus type 1 (HIV-1) from entering host cells. This linear 36-mer synthetic peptide is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1-infected individuals and AIDS patients with multidrug-resistant HIV infections. Although enfuvirtide is an efficient anti-HIV-1 drug, its clinical use is limited by a short plasma half-life, i.e., approximately 2 h, which requires twice-daily subcutaneous injections, often resulting in skin sensitivity reaction side effects at the injection sites. Ultimately, 80% of patients stop enfuvirtide treatment within 6 months because of these side effects. We report on the development of long-lasting enfuvirtide conjugates by the use of the site-specific conjugation of enfuvirtide to an antithrombin-binding carrier pentasaccharide (CP) through polyethylene glycol (PEG) linkers of various lengths. These conjugates showed consistent and broad anti-HIV-1 activity in the nanomolar range. The coupling of the CP to enfuvirtide only moderately affected the in vitro anti-HIV-1 activity in the presence of antithrombin. Most importantly, one of these conjugates, enfuvirtide-PEG(12)-CP (EP40111), exhibited a prolonged elimination half-life of more than 10 h in rat plasma compared to the half-life of native enfuvirtide, which was 2.8 h. On the basis of the pharmacokinetic properties of antithrombin-binding pentasaccharides, the anticipated half-life of EP40111 in humans would putatively be about 120 h, which would allow subcutaneous injection once a week instead of twice daily. In conclusion, EP40111 is a promising compound with strong potency as a novel long-lasting anti-HIV-1 drug.
|
Antiviral activity against HIV1 US2 clade B, R5 in human PBMC assessed as p24 antigen level by ELISA
|
Human immunodeficiency virus 1
|
0.3
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Long-lasting enfuvirtide carrier pentasaccharide conjugates with potent anti-human immunodeficiency virus type 1 activity.
Year : 2010
Volume : 54
Issue : 1
First Page : 134
Last Page : 142
Authors : Huet T, Kerbarh O, Schols D, Clayette P, Gauchet C, Dubreucq G, Vincent L, Bompais H, Mazinghien R, Querolle O, Salvador A, Lemoine J, Lucidi B, Balzarini J, Petitou M.
Abstract : Enfuvirtide (also known as Fuzeon, T-20, or DP-178) is an antiretroviral fusion inhibitor which prevents human immunodeficiency virus type 1 (HIV-1) from entering host cells. This linear 36-mer synthetic peptide is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1-infected individuals and AIDS patients with multidrug-resistant HIV infections. Although enfuvirtide is an efficient anti-HIV-1 drug, its clinical use is limited by a short plasma half-life, i.e., approximately 2 h, which requires twice-daily subcutaneous injections, often resulting in skin sensitivity reaction side effects at the injection sites. Ultimately, 80% of patients stop enfuvirtide treatment within 6 months because of these side effects. We report on the development of long-lasting enfuvirtide conjugates by the use of the site-specific conjugation of enfuvirtide to an antithrombin-binding carrier pentasaccharide (CP) through polyethylene glycol (PEG) linkers of various lengths. These conjugates showed consistent and broad anti-HIV-1 activity in the nanomolar range. The coupling of the CP to enfuvirtide only moderately affected the in vitro anti-HIV-1 activity in the presence of antithrombin. Most importantly, one of these conjugates, enfuvirtide-PEG(12)-CP (EP40111), exhibited a prolonged elimination half-life of more than 10 h in rat plasma compared to the half-life of native enfuvirtide, which was 2.8 h. On the basis of the pharmacokinetic properties of antithrombin-binding pentasaccharides, the anticipated half-life of EP40111 in humans would putatively be about 120 h, which would allow subcutaneous injection once a week instead of twice daily. In conclusion, EP40111 is a promising compound with strong potency as a novel long-lasting anti-HIV-1 drug.
|
Antiviral activity against HIV1 ETH2220 in human PBMC assessed as p24 antigen level by ELISA
|
Human immunodeficiency virus 1
|
3.6
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Long-lasting enfuvirtide carrier pentasaccharide conjugates with potent anti-human immunodeficiency virus type 1 activity.
Year : 2010
Volume : 54
Issue : 1
First Page : 134
Last Page : 142
Authors : Huet T, Kerbarh O, Schols D, Clayette P, Gauchet C, Dubreucq G, Vincent L, Bompais H, Mazinghien R, Querolle O, Salvador A, Lemoine J, Lucidi B, Balzarini J, Petitou M.
Abstract : Enfuvirtide (also known as Fuzeon, T-20, or DP-178) is an antiretroviral fusion inhibitor which prevents human immunodeficiency virus type 1 (HIV-1) from entering host cells. This linear 36-mer synthetic peptide is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1-infected individuals and AIDS patients with multidrug-resistant HIV infections. Although enfuvirtide is an efficient anti-HIV-1 drug, its clinical use is limited by a short plasma half-life, i.e., approximately 2 h, which requires twice-daily subcutaneous injections, often resulting in skin sensitivity reaction side effects at the injection sites. Ultimately, 80% of patients stop enfuvirtide treatment within 6 months because of these side effects. We report on the development of long-lasting enfuvirtide conjugates by the use of the site-specific conjugation of enfuvirtide to an antithrombin-binding carrier pentasaccharide (CP) through polyethylene glycol (PEG) linkers of various lengths. These conjugates showed consistent and broad anti-HIV-1 activity in the nanomolar range. The coupling of the CP to enfuvirtide only moderately affected the in vitro anti-HIV-1 activity in the presence of antithrombin. Most importantly, one of these conjugates, enfuvirtide-PEG(12)-CP (EP40111), exhibited a prolonged elimination half-life of more than 10 h in rat plasma compared to the half-life of native enfuvirtide, which was 2.8 h. On the basis of the pharmacokinetic properties of antithrombin-binding pentasaccharides, the anticipated half-life of EP40111 in humans would putatively be about 120 h, which would allow subcutaneous injection once a week instead of twice daily. In conclusion, EP40111 is a promising compound with strong potency as a novel long-lasting anti-HIV-1 drug.
|
Antiviral activity against HIV1 DJ259 in human PBMC assessed as p24 antigen level by ELISA
|
Human immunodeficiency virus 1
|
3.7
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Long-lasting enfuvirtide carrier pentasaccharide conjugates with potent anti-human immunodeficiency virus type 1 activity.
Year : 2010
Volume : 54
Issue : 1
First Page : 134
Last Page : 142
Authors : Huet T, Kerbarh O, Schols D, Clayette P, Gauchet C, Dubreucq G, Vincent L, Bompais H, Mazinghien R, Querolle O, Salvador A, Lemoine J, Lucidi B, Balzarini J, Petitou M.
Abstract : Enfuvirtide (also known as Fuzeon, T-20, or DP-178) is an antiretroviral fusion inhibitor which prevents human immunodeficiency virus type 1 (HIV-1) from entering host cells. This linear 36-mer synthetic peptide is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1-infected individuals and AIDS patients with multidrug-resistant HIV infections. Although enfuvirtide is an efficient anti-HIV-1 drug, its clinical use is limited by a short plasma half-life, i.e., approximately 2 h, which requires twice-daily subcutaneous injections, often resulting in skin sensitivity reaction side effects at the injection sites. Ultimately, 80% of patients stop enfuvirtide treatment within 6 months because of these side effects. We report on the development of long-lasting enfuvirtide conjugates by the use of the site-specific conjugation of enfuvirtide to an antithrombin-binding carrier pentasaccharide (CP) through polyethylene glycol (PEG) linkers of various lengths. These conjugates showed consistent and broad anti-HIV-1 activity in the nanomolar range. The coupling of the CP to enfuvirtide only moderately affected the in vitro anti-HIV-1 activity in the presence of antithrombin. Most importantly, one of these conjugates, enfuvirtide-PEG(12)-CP (EP40111), exhibited a prolonged elimination half-life of more than 10 h in rat plasma compared to the half-life of native enfuvirtide, which was 2.8 h. On the basis of the pharmacokinetic properties of antithrombin-binding pentasaccharides, the anticipated half-life of EP40111 in humans would putatively be about 120 h, which would allow subcutaneous injection once a week instead of twice daily. In conclusion, EP40111 is a promising compound with strong potency as a novel long-lasting anti-HIV-1 drug.
|
Antagonist activity at CCR5 receptor expressed in HeLa-P4 cells co-expressing CD4 assessed as inhibition of infusion to HIV gp120 expressed in CHO-tat10 cells after 20 hrs by cell-cell fusion assay
|
None
|
0.2
nM
|
|
Journal : J. Med. Chem.
Title : An imidazopiperidine series of CCR5 antagonists for the treatment of HIV: the discovery of N-{(1S)-1-(3-fluorophenyl)-3-[(3-endo)-3-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]propyl}acetamide (PF-232798).
Year : 2011
Volume : 54
Issue : 1
First Page : 67
Last Page : 77
Authors : Stupple PA, Batchelor DV, Corless M, Dorr PK, Ellis D, Fenwick DR, Galan SR, Jones RM, Mason HJ, Middleton DS, Perros M, Perruccio F, Platts MY, Pryde DC, Rodrigues D, Smith NN, Stephenson PT, Webster R, Westby M, Wood A.
Abstract : Preventing entry of HIV into human host cells has emerged as an attractive approach to controlling viral replication. Maraviroc 1 is an approved antagonist of the human CCR5 receptor which prevents the entry of HIV. Herein, we report the design and discovery of a series of imidazopiperidine CCR5 antagonists which retain the attractive antiviral profile and window over hERG activity of maraviroc 1, combined with improved absorption profiles in rat and dog. Furthermore, this series of compounds has been shown to retain activity against a laboratory generated maraviroc-resistant HIV-1 strain, which indicates an alternative resistance profile to that of maraviroc 1. Compound 41f (PF-232798) was selected as a clinical candidate from the imidazopiperidine series and is currently in phase II clinical trials.
|
Displacement of [3H]-dofetilide from human ERG expressed in HEK293 cells at 300 nM
|
Homo sapiens
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : An imidazopiperidine series of CCR5 antagonists for the treatment of HIV: the discovery of N-{(1S)-1-(3-fluorophenyl)-3-[(3-endo)-3-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]propyl}acetamide (PF-232798).
Year : 2011
Volume : 54
Issue : 1
First Page : 67
Last Page : 77
Authors : Stupple PA, Batchelor DV, Corless M, Dorr PK, Ellis D, Fenwick DR, Galan SR, Jones RM, Mason HJ, Middleton DS, Perros M, Perruccio F, Platts MY, Pryde DC, Rodrigues D, Smith NN, Stephenson PT, Webster R, Westby M, Wood A.
Abstract : Preventing entry of HIV into human host cells has emerged as an attractive approach to controlling viral replication. Maraviroc 1 is an approved antagonist of the human CCR5 receptor which prevents the entry of HIV. Herein, we report the design and discovery of a series of imidazopiperidine CCR5 antagonists which retain the attractive antiviral profile and window over hERG activity of maraviroc 1, combined with improved absorption profiles in rat and dog. Furthermore, this series of compounds has been shown to retain activity against a laboratory generated maraviroc-resistant HIV-1 strain, which indicates an alternative resistance profile to that of maraviroc 1. Compound 41f (PF-232798) was selected as a clinical candidate from the imidazopiperidine series and is currently in phase II clinical trials.
|
Binding affinity to CCR5
|
None
|
25.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Screening for GPCR Ligands Using Surface Plasmon Resonance.
Year : 2011
Volume : 2
Issue : 7
First Page : 549
Last Page : 554
Authors : Navratilova I, Besnard J, Hopkins AL.
Abstract : G-protein coupled receptors (GPCRs) are a class of drug targets of primary importance. However, receptor assays are based on measurement of either ligand displacement or downstream functional responses, rather than direct observation of ligand binding. Issues of allosteric modulation, probe dependence, and functional selectivity create challenges in selecting suitable assays formats. Therefore, a method that directly measures GPCR-ligand interactions, independent of binding site, probe, and signaling pathway would be a useful primary and orthogonal screening method. We have developed a GPCR biosensor assay protocol that offers the opportunity for high-throughput label-free screening that directly measures GPCR-ligand interactions. The biosensor-based direct screening method identifies the interaction of both orthosteric and allosteric ligands with solubilized, native GPCRs, in a label-free and cell-free environment, thus overcoming the limitations of indirect and displacement assay methods. We exemplify the method by the discovery of novel ligands for the chemokine receptor, CCR5, that are ligand efficient fragments.
|
Antiviral activity against HIV1 clade G (BCF-DIOUM) infected in human PBMCs assessed as inhibition of p24 antigen production by ELISA
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : New nitrogen containing substituents at the indole-2-carboxamide yield high potent and broad spectrum indolylarylsulfone HIV-1 non-nucleoside reverse transcriptase inhibitors.
Year : 2012
Volume : 55
Issue : 14
First Page : 6634
Last Page : 6638
Authors : La Regina G, Coluccia A, Brancale A, Piscitelli F, Famiglini V, Cosconati S, Maga G, Samuele A, Gonzalez E, Clotet B, Schols D, Esté JA, Novellino E, Silvestri R.
Abstract : New indolylarylsulfone (IAS) derivatives bearing nitrogen containing substituents at the indole-2-carboxamide inhibited the HIV-1 WT in MT-4 cells at low nanomolar concentrations. In particular, compound 9 was uniformly effective against the mutant Y181C, Y188L, and K103N HIV-1 strains; it was highly active against the multidrug resistant mutant IRLL98 HIV-1 strain bearing the K101Q, Y181C, and G190A mutations conferring resistance to NVP, DLV, and EFV and several HIV-1 clades A in PBMC.
|
Antiviral activity against HIV1 clade F (BZ162) infected in human PBMCs assessed as inhibition of p24 antigen production by ELISA
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : New nitrogen containing substituents at the indole-2-carboxamide yield high potent and broad spectrum indolylarylsulfone HIV-1 non-nucleoside reverse transcriptase inhibitors.
Year : 2012
Volume : 55
Issue : 14
First Page : 6634
Last Page : 6638
Authors : La Regina G, Coluccia A, Brancale A, Piscitelli F, Famiglini V, Cosconati S, Maga G, Samuele A, Gonzalez E, Clotet B, Schols D, Esté JA, Novellino E, Silvestri R.
Abstract : New indolylarylsulfone (IAS) derivatives bearing nitrogen containing substituents at the indole-2-carboxamide inhibited the HIV-1 WT in MT-4 cells at low nanomolar concentrations. In particular, compound 9 was uniformly effective against the mutant Y181C, Y188L, and K103N HIV-1 strains; it was highly active against the multidrug resistant mutant IRLL98 HIV-1 strain bearing the K101Q, Y181C, and G190A mutations conferring resistance to NVP, DLV, and EFV and several HIV-1 clades A in PBMC.
|
Antiviral activity against HIV1 clade B (BaL) infected in human PBMCs assessed as inhibition of p24 antigen production by ELISA
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : New nitrogen containing substituents at the indole-2-carboxamide yield high potent and broad spectrum indolylarylsulfone HIV-1 non-nucleoside reverse transcriptase inhibitors.
Year : 2012
Volume : 55
Issue : 14
First Page : 6634
Last Page : 6638
Authors : La Regina G, Coluccia A, Brancale A, Piscitelli F, Famiglini V, Cosconati S, Maga G, Samuele A, Gonzalez E, Clotet B, Schols D, Esté JA, Novellino E, Silvestri R.
Abstract : New indolylarylsulfone (IAS) derivatives bearing nitrogen containing substituents at the indole-2-carboxamide inhibited the HIV-1 WT in MT-4 cells at low nanomolar concentrations. In particular, compound 9 was uniformly effective against the mutant Y181C, Y188L, and K103N HIV-1 strains; it was highly active against the multidrug resistant mutant IRLL98 HIV-1 strain bearing the K101Q, Y181C, and G190A mutations conferring resistance to NVP, DLV, and EFV and several HIV-1 clades A in PBMC.
|
Antiviral activity against HIV1 clade A (UG273) infected in human PBMCs assessed as inhibition of p24 antigen production by ELISA
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : New nitrogen containing substituents at the indole-2-carboxamide yield high potent and broad spectrum indolylarylsulfone HIV-1 non-nucleoside reverse transcriptase inhibitors.
Year : 2012
Volume : 55
Issue : 14
First Page : 6634
Last Page : 6638
Authors : La Regina G, Coluccia A, Brancale A, Piscitelli F, Famiglini V, Cosconati S, Maga G, Samuele A, Gonzalez E, Clotet B, Schols D, Esté JA, Novellino E, Silvestri R.
Abstract : New indolylarylsulfone (IAS) derivatives bearing nitrogen containing substituents at the indole-2-carboxamide inhibited the HIV-1 WT in MT-4 cells at low nanomolar concentrations. In particular, compound 9 was uniformly effective against the mutant Y181C, Y188L, and K103N HIV-1 strains; it was highly active against the multidrug resistant mutant IRLL98 HIV-1 strain bearing the K101Q, Y181C, and G190A mutations conferring resistance to NVP, DLV, and EFV and several HIV-1 clades A in PBMC.
|
Antiviral activity against HIV1 clade A/E (ID12) infected in human PBMCs assessed as inhibition of p24 antigen production by ELISA
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : New nitrogen containing substituents at the indole-2-carboxamide yield high potent and broad spectrum indolylarylsulfone HIV-1 non-nucleoside reverse transcriptase inhibitors.
Year : 2012
Volume : 55
Issue : 14
First Page : 6634
Last Page : 6638
Authors : La Regina G, Coluccia A, Brancale A, Piscitelli F, Famiglini V, Cosconati S, Maga G, Samuele A, Gonzalez E, Clotet B, Schols D, Esté JA, Novellino E, Silvestri R.
Abstract : New indolylarylsulfone (IAS) derivatives bearing nitrogen containing substituents at the indole-2-carboxamide inhibited the HIV-1 WT in MT-4 cells at low nanomolar concentrations. In particular, compound 9 was uniformly effective against the mutant Y181C, Y188L, and K103N HIV-1 strains; it was highly active against the multidrug resistant mutant IRLL98 HIV-1 strain bearing the K101Q, Y181C, and G190A mutations conferring resistance to NVP, DLV, and EFV and several HIV-1 clades A in PBMC.
|
Antiviral activity against HIV1 clade C (SM145) infected in human PBMCs assessed as inhibition of p24 antigen production by ELISA
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : New nitrogen containing substituents at the indole-2-carboxamide yield high potent and broad spectrum indolylarylsulfone HIV-1 non-nucleoside reverse transcriptase inhibitors.
Year : 2012
Volume : 55
Issue : 14
First Page : 6634
Last Page : 6638
Authors : La Regina G, Coluccia A, Brancale A, Piscitelli F, Famiglini V, Cosconati S, Maga G, Samuele A, Gonzalez E, Clotet B, Schols D, Esté JA, Novellino E, Silvestri R.
Abstract : New indolylarylsulfone (IAS) derivatives bearing nitrogen containing substituents at the indole-2-carboxamide inhibited the HIV-1 WT in MT-4 cells at low nanomolar concentrations. In particular, compound 9 was uniformly effective against the mutant Y181C, Y188L, and K103N HIV-1 strains; it was highly active against the multidrug resistant mutant IRLL98 HIV-1 strain bearing the K101Q, Y181C, and G190A mutations conferring resistance to NVP, DLV, and EFV and several HIV-1 clades A in PBMC.
|
Antiviral activity against HIV1 clade C (DJ259) infected in human PBMCs assessed as inhibition of p24 antigen production by ELISA
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : New nitrogen containing substituents at the indole-2-carboxamide yield high potent and broad spectrum indolylarylsulfone HIV-1 non-nucleoside reverse transcriptase inhibitors.
Year : 2012
Volume : 55
Issue : 14
First Page : 6634
Last Page : 6638
Authors : La Regina G, Coluccia A, Brancale A, Piscitelli F, Famiglini V, Cosconati S, Maga G, Samuele A, Gonzalez E, Clotet B, Schols D, Esté JA, Novellino E, Silvestri R.
Abstract : New indolylarylsulfone (IAS) derivatives bearing nitrogen containing substituents at the indole-2-carboxamide inhibited the HIV-1 WT in MT-4 cells at low nanomolar concentrations. In particular, compound 9 was uniformly effective against the mutant Y181C, Y188L, and K103N HIV-1 strains; it was highly active against the multidrug resistant mutant IRLL98 HIV-1 strain bearing the K101Q, Y181C, and G190A mutations conferring resistance to NVP, DLV, and EFV and several HIV-1 clades A in PBMC.
|
Antiviral activity against HIV1 clade D (UG270) infected in human PBMCs assessed as inhibition of p24 antigen production by ELISA
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : New nitrogen containing substituents at the indole-2-carboxamide yield high potent and broad spectrum indolylarylsulfone HIV-1 non-nucleoside reverse transcriptase inhibitors.
Year : 2012
Volume : 55
Issue : 14
First Page : 6634
Last Page : 6638
Authors : La Regina G, Coluccia A, Brancale A, Piscitelli F, Famiglini V, Cosconati S, Maga G, Samuele A, Gonzalez E, Clotet B, Schols D, Esté JA, Novellino E, Silvestri R.
Abstract : New indolylarylsulfone (IAS) derivatives bearing nitrogen containing substituents at the indole-2-carboxamide inhibited the HIV-1 WT in MT-4 cells at low nanomolar concentrations. In particular, compound 9 was uniformly effective against the mutant Y181C, Y188L, and K103N HIV-1 strains; it was highly active against the multidrug resistant mutant IRLL98 HIV-1 strain bearing the K101Q, Y181C, and G190A mutations conferring resistance to NVP, DLV, and EFV and several HIV-1 clades A in PBMC.
|
Binding affinity to CCR5
|
None
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Chemokine receptor antagonists.
Year : 2012
Volume : 55
Issue : 22
First Page : 9363
Last Page : 9392
Authors : Pease J, Horuk R.
|
Antagonist activity against CXCR5 expressed in U87.CD.CXCR5 cells assessed as inhibition of CCL3L1-induced calcium signaling incubated for 10 mins by FLIPR
|
Homo sapiens
|
0.0024
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : HIV-1 X4 activities of polycationic "viologen" based dendrimers by interaction with the chemokine receptor CXCR4: study of structure-activity relationship.
Year : 2012
Volume : 55
Issue : 23
First Page : 10405
Last Page : 10413
Authors : Asaftei S, Huskens D, Schols D.
Abstract : A series of "viologen" based dendrimers with polycationic scaffold carrying 10, 18, 26, 42, and 90 charges per molecule were used to determine the structure-activity relationship (SAR) with regard to HIV-1 inhibitory activity. The studies involved five compounds with a high activity against HIV-1 already utilized in our previous study (1) and five new dendrimers. Such dendrimers block HIV-1 entry into the cell, indicating that they bind to HIV-1 surface proteins and/or on the host cell receptors required for entry. The increasing positive character of dendrimers leads to more cytotoxicity. The 10 charges dendrimers (1, 6) have less influence on the cell viability but low inhibition of the binding of the CXCR4 mAb clone 1D9. Thus, dendrimers with 18 charges (2, 7) are the most promising CXCR4 imaging probes. We report the design, synthesis, and biological activity of new HIV-1 inhibitors that are conceptually distinct from those of the existing HIV-1 inhibitors.
|
Antiviral activity against Human immunodeficiency virus 1 clade B isolate BaL infected in PHA-stimulated human PBMC after 10 days by ELISA
|
Human immunodeficiency virus 1
|
13.9
nM
|
|
Journal : J. Med. Chem.
Title : Design of substituted imidazolidinylpiperidinylbenzoic acids as chemokine receptor 5 antagonists: potent inhibitors of R5 HIV-1 replication.
Year : 2013
Volume : 56
Issue : 20
First Page : 8049
Last Page : 8065
Authors : Skerlj R, Bridger G, Zhou Y, Bourque E, McEachern E, Metz M, Harwig C, Li TS, Yang W, Bogucki D, Zhu Y, Langille J, Veale D, Ba T, Bey M, Baird I, Kaller A, Krumpak M, Leitch D, Satori M, Vocadlo K, Guay D, Nan S, Yee H, Crawford J, Chen G, Wilson T, Carpenter B, Gauthier D, Macfarland R, Mosi R, Bodart V, Wong R, Fricker S, Schols D.
Abstract : The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure-activity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, 6d and 6h were selected for further development.
|
Antiviral activity against Human immunodeficiency virus 1 clade B isolate CI#19 infected in PHA-stimulated human PBMC after 10 days by ELISA
|
Human immunodeficiency virus 1
|
1.3
nM
|
|
Journal : J. Med. Chem.
Title : Design of substituted imidazolidinylpiperidinylbenzoic acids as chemokine receptor 5 antagonists: potent inhibitors of R5 HIV-1 replication.
Year : 2013
Volume : 56
Issue : 20
First Page : 8049
Last Page : 8065
Authors : Skerlj R, Bridger G, Zhou Y, Bourque E, McEachern E, Metz M, Harwig C, Li TS, Yang W, Bogucki D, Zhu Y, Langille J, Veale D, Ba T, Bey M, Baird I, Kaller A, Krumpak M, Leitch D, Satori M, Vocadlo K, Guay D, Nan S, Yee H, Crawford J, Chen G, Wilson T, Carpenter B, Gauthier D, Macfarland R, Mosi R, Bodart V, Wong R, Fricker S, Schols D.
Abstract : The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure-activity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, 6d and 6h were selected for further development.
|
Antiviral activity against Human immunodeficiency virus 1 clade B isolate CI#15 infected in PHA-stimulated human PBMC after 10 days by ELISA
|
Human immunodeficiency virus 1
|
1.4
nM
|
|
Journal : J. Med. Chem.
Title : Design of substituted imidazolidinylpiperidinylbenzoic acids as chemokine receptor 5 antagonists: potent inhibitors of R5 HIV-1 replication.
Year : 2013
Volume : 56
Issue : 20
First Page : 8049
Last Page : 8065
Authors : Skerlj R, Bridger G, Zhou Y, Bourque E, McEachern E, Metz M, Harwig C, Li TS, Yang W, Bogucki D, Zhu Y, Langille J, Veale D, Ba T, Bey M, Baird I, Kaller A, Krumpak M, Leitch D, Satori M, Vocadlo K, Guay D, Nan S, Yee H, Crawford J, Chen G, Wilson T, Carpenter B, Gauthier D, Macfarland R, Mosi R, Bodart V, Wong R, Fricker S, Schols D.
Abstract : The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure-activity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, 6d and 6h were selected for further development.
|
Antiviral activity against Human immunodeficiency virus 1 clade B isolate Ada infected in PHA-stimulated human PBMC after 10 days by ELISA
|
Human immunodeficiency virus 1
|
0.3
nM
|
|
Journal : J. Med. Chem.
Title : Design of substituted imidazolidinylpiperidinylbenzoic acids as chemokine receptor 5 antagonists: potent inhibitors of R5 HIV-1 replication.
Year : 2013
Volume : 56
Issue : 20
First Page : 8049
Last Page : 8065
Authors : Skerlj R, Bridger G, Zhou Y, Bourque E, McEachern E, Metz M, Harwig C, Li TS, Yang W, Bogucki D, Zhu Y, Langille J, Veale D, Ba T, Bey M, Baird I, Kaller A, Krumpak M, Leitch D, Satori M, Vocadlo K, Guay D, Nan S, Yee H, Crawford J, Chen G, Wilson T, Carpenter B, Gauthier D, Macfarland R, Mosi R, Bodart V, Wong R, Fricker S, Schols D.
Abstract : The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure-activity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, 6d and 6h were selected for further development.
|
Antiviral activity against Human immunodeficiency virus 1 clade B isolate SF162 infected in PHA-stimulated human PBMC after 10 days by ELISA
|
Human immunodeficiency virus 1
|
18.6
nM
|
|
Journal : J. Med. Chem.
Title : Design of substituted imidazolidinylpiperidinylbenzoic acids as chemokine receptor 5 antagonists: potent inhibitors of R5 HIV-1 replication.
Year : 2013
Volume : 56
Issue : 20
First Page : 8049
Last Page : 8065
Authors : Skerlj R, Bridger G, Zhou Y, Bourque E, McEachern E, Metz M, Harwig C, Li TS, Yang W, Bogucki D, Zhu Y, Langille J, Veale D, Ba T, Bey M, Baird I, Kaller A, Krumpak M, Leitch D, Satori M, Vocadlo K, Guay D, Nan S, Yee H, Crawford J, Chen G, Wilson T, Carpenter B, Gauthier D, Macfarland R, Mosi R, Bodart V, Wong R, Fricker S, Schols D.
Abstract : The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure-activity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, 6d and 6h were selected for further development.
|
Antiviral activity against Human immunodeficiency virus 1 clade O isolate I-2478B infected in PHA-stimulated human PBMC after 10 days by ELISA
|
Human immunodeficiency virus 1
|
6.4
nM
|
|
Journal : J. Med. Chem.
Title : Design of substituted imidazolidinylpiperidinylbenzoic acids as chemokine receptor 5 antagonists: potent inhibitors of R5 HIV-1 replication.
Year : 2013
Volume : 56
Issue : 20
First Page : 8049
Last Page : 8065
Authors : Skerlj R, Bridger G, Zhou Y, Bourque E, McEachern E, Metz M, Harwig C, Li TS, Yang W, Bogucki D, Zhu Y, Langille J, Veale D, Ba T, Bey M, Baird I, Kaller A, Krumpak M, Leitch D, Satori M, Vocadlo K, Guay D, Nan S, Yee H, Crawford J, Chen G, Wilson T, Carpenter B, Gauthier D, Macfarland R, Mosi R, Bodart V, Wong R, Fricker S, Schols D.
Abstract : The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure-activity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, 6d and 6h were selected for further development.
|
Antiviral activity against Human immunodeficiency virus 1 clade G isolate BZ163 infected in PHA-stimulated human PBMC after 10 days by ELISA
|
Human immunodeficiency virus 1
|
14.8
nM
|
|
Journal : J. Med. Chem.
Title : Design of substituted imidazolidinylpiperidinylbenzoic acids as chemokine receptor 5 antagonists: potent inhibitors of R5 HIV-1 replication.
Year : 2013
Volume : 56
Issue : 20
First Page : 8049
Last Page : 8065
Authors : Skerlj R, Bridger G, Zhou Y, Bourque E, McEachern E, Metz M, Harwig C, Li TS, Yang W, Bogucki D, Zhu Y, Langille J, Veale D, Ba T, Bey M, Baird I, Kaller A, Krumpak M, Leitch D, Satori M, Vocadlo K, Guay D, Nan S, Yee H, Crawford J, Chen G, Wilson T, Carpenter B, Gauthier D, Macfarland R, Mosi R, Bodart V, Wong R, Fricker S, Schols D.
Abstract : The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure-activity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, 6d and 6h were selected for further development.
|
Antiviral activity against Human immunodeficiency virus 1 clade E isolate ID12 infected in PHA-stimulated human PBMC after 10 days by ELISA
|
Human immunodeficiency virus 1
|
14.6
nM
|
|
Journal : J. Med. Chem.
Title : Design of substituted imidazolidinylpiperidinylbenzoic acids as chemokine receptor 5 antagonists: potent inhibitors of R5 HIV-1 replication.
Year : 2013
Volume : 56
Issue : 20
First Page : 8049
Last Page : 8065
Authors : Skerlj R, Bridger G, Zhou Y, Bourque E, McEachern E, Metz M, Harwig C, Li TS, Yang W, Bogucki D, Zhu Y, Langille J, Veale D, Ba T, Bey M, Baird I, Kaller A, Krumpak M, Leitch D, Satori M, Vocadlo K, Guay D, Nan S, Yee H, Crawford J, Chen G, Wilson T, Carpenter B, Gauthier D, Macfarland R, Mosi R, Bodart V, Wong R, Fricker S, Schols D.
Abstract : The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure-activity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, 6d and 6h were selected for further development.
|
Antiviral activity against Human immunodeficiency virus 1 clade C isolate ETH2220 infected in PHA-stimulated human PBMC after 10 days by ELISA
|
Human immunodeficiency virus 1
|
50.4
nM
|
|
Journal : J. Med. Chem.
Title : Design of substituted imidazolidinylpiperidinylbenzoic acids as chemokine receptor 5 antagonists: potent inhibitors of R5 HIV-1 replication.
Year : 2013
Volume : 56
Issue : 20
First Page : 8049
Last Page : 8065
Authors : Skerlj R, Bridger G, Zhou Y, Bourque E, McEachern E, Metz M, Harwig C, Li TS, Yang W, Bogucki D, Zhu Y, Langille J, Veale D, Ba T, Bey M, Baird I, Kaller A, Krumpak M, Leitch D, Satori M, Vocadlo K, Guay D, Nan S, Yee H, Crawford J, Chen G, Wilson T, Carpenter B, Gauthier D, Macfarland R, Mosi R, Bodart V, Wong R, Fricker S, Schols D.
Abstract : The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure-activity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, 6d and 6h were selected for further development.
|
Antiviral activity against Human immunodeficiency virus 1 clade B isolate US2 infected in PHA-stimulated human PBMC after 10 days by ELISA
|
Human immunodeficiency virus 1
|
0.3
nM
|
|
Journal : J. Med. Chem.
Title : Design of substituted imidazolidinylpiperidinylbenzoic acids as chemokine receptor 5 antagonists: potent inhibitors of R5 HIV-1 replication.
Year : 2013
Volume : 56
Issue : 20
First Page : 8049
Last Page : 8065
Authors : Skerlj R, Bridger G, Zhou Y, Bourque E, McEachern E, Metz M, Harwig C, Li TS, Yang W, Bogucki D, Zhu Y, Langille J, Veale D, Ba T, Bey M, Baird I, Kaller A, Krumpak M, Leitch D, Satori M, Vocadlo K, Guay D, Nan S, Yee H, Crawford J, Chen G, Wilson T, Carpenter B, Gauthier D, Macfarland R, Mosi R, Bodart V, Wong R, Fricker S, Schols D.
Abstract : The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure-activity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, 6d and 6h were selected for further development.
|
Antiviral activity against Human immunodeficiency virus 1 clade A isolate UG273 infected in PHA-stimulated human PBMC after 10 days by ELISA
|
Human immunodeficiency virus 1
|
7.1
nM
|
|
Journal : J. Med. Chem.
Title : Design of substituted imidazolidinylpiperidinylbenzoic acids as chemokine receptor 5 antagonists: potent inhibitors of R5 HIV-1 replication.
Year : 2013
Volume : 56
Issue : 20
First Page : 8049
Last Page : 8065
Authors : Skerlj R, Bridger G, Zhou Y, Bourque E, McEachern E, Metz M, Harwig C, Li TS, Yang W, Bogucki D, Zhu Y, Langille J, Veale D, Ba T, Bey M, Baird I, Kaller A, Krumpak M, Leitch D, Satori M, Vocadlo K, Guay D, Nan S, Yee H, Crawford J, Chen G, Wilson T, Carpenter B, Gauthier D, Macfarland R, Mosi R, Bodart V, Wong R, Fricker S, Schols D.
Abstract : The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure-activity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, 6d and 6h were selected for further development.
|
Antiviral activity against HIV-1 infected in human SupT1 cells assessed as inhibition of viral infectivity after 48 hrs by luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
1.1
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis, and biological evaluation of novel piperidine-4-carboxamide derivatives as potent CCR5 inhibitors.
Year : 2014
Volume : 71
First Page : 259
Last Page : 266
Authors : Hu S, Gu Q, Wang Z, Weng Z, Cai Y, Dong X, Hu Y, Liu T, Xie X.
Abstract : Based on a putative 'Y shape' pharmacophore model of CCR5 inhibitors, a series of novel piperidine-4-carboxamide derivatives were designed and synthesized using a group-reverse strategy. Among synthesized target compounds, 16g (IC₅₀ = 25.73 nM) and 16i (IC₅₀ = 25.53 nM) showed equivalent inhibitory activity against CCR5 to that of the positive control maraviroc (IC₅₀ = 25.43 nM) in calcium mobilization assay. Selected compounds were further tested for their antiviral activity in HIV-1 single cycle assay. Two compounds, 16g and 16i, displayed antiviral activity with IC₅₀ values of 73.01 nM and 94.10 nM, respectively. Additionally, the pharmacokinetic properties and inhibitory potency against hERG of 16g were evaluated, providing a foundation for ongoing optimization.
|
Inhibition of CCR5 (unknown origin) expressed in CHO cells assessed as inhibition of RANTES-induced intracellular Ca2+ mobilization after 10 mins by Fluo-4 AM staining-based fluorescence assay
|
Homo sapiens
|
25.43
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis, and biological evaluation of novel piperidine-4-carboxamide derivatives as potent CCR5 inhibitors.
Year : 2014
Volume : 71
First Page : 259
Last Page : 266
Authors : Hu S, Gu Q, Wang Z, Weng Z, Cai Y, Dong X, Hu Y, Liu T, Xie X.
Abstract : Based on a putative 'Y shape' pharmacophore model of CCR5 inhibitors, a series of novel piperidine-4-carboxamide derivatives were designed and synthesized using a group-reverse strategy. Among synthesized target compounds, 16g (IC₅₀ = 25.73 nM) and 16i (IC₅₀ = 25.53 nM) showed equivalent inhibitory activity against CCR5 to that of the positive control maraviroc (IC₅₀ = 25.43 nM) in calcium mobilization assay. Selected compounds were further tested for their antiviral activity in HIV-1 single cycle assay. Two compounds, 16g and 16i, displayed antiviral activity with IC₅₀ values of 73.01 nM and 94.10 nM, respectively. Additionally, the pharmacokinetic properties and inhibitory potency against hERG of 16g were evaluated, providing a foundation for ongoing optimization.
|
Antagonist activity against CCR5 receptor in human TZM-bl cells assessed as inhibition of HIV-1 MGC26-induced cell-cell fusion between viral envelope protein expressing human HEK293 cells to TZM-bl cells after 48 hrs by luciferase reporter gene assay
|
Homo sapiens
|
0.37
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Preparation and activities of macromolecule conjugates of the CCR5 antagonist Maraviroc.
Year : 2014
Volume : 5
Issue : 2
First Page : 133
Last Page : 137
Authors : Asano S, Gavrilyuk J, Burton DR, Barbas CF.
Abstract : CCR5 antagonists are among the most advanced approaches in HIV therapy and may also be relevant to treatment of graft-versus-host disease and Staphylococcus aureus infection. To expand the potential of the only approved CCR5 antagonist, Maraviroc, we studied derivatives that would enable functional linkage of Maraviroc to long-lived carriers. Through targeted synthesis, we discovered an effective linkage site on Maraviroc and demonstrate the potential of these derivatives to prepare potent chemically programmed antibodies and PEGylated derivatives. The resulting compounds effectively neutralized a variety of HIV-1 isolates. Both chemically programmed antibody and PEGylation approaches extend the neutralization activity of serum circulating Maraviroc. Derivation of a successful conjugation strategy for Maraviroc should further enable its use in chemically programmed vaccines, novel bispecific antibodies, and topical microbicides.
|
Antagonist activity against CCR5 receptor in human TZM-bl cells assessed as inhibition of HIV-1 92RW-induced cell-cell fusion between viral envelope protein expressing human HEK293 cells to TZM-bl cells after 48 hrs by luciferase reporter gene assay
|
Homo sapiens
|
1.3
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Preparation and activities of macromolecule conjugates of the CCR5 antagonist Maraviroc.
Year : 2014
Volume : 5
Issue : 2
First Page : 133
Last Page : 137
Authors : Asano S, Gavrilyuk J, Burton DR, Barbas CF.
Abstract : CCR5 antagonists are among the most advanced approaches in HIV therapy and may also be relevant to treatment of graft-versus-host disease and Staphylococcus aureus infection. To expand the potential of the only approved CCR5 antagonist, Maraviroc, we studied derivatives that would enable functional linkage of Maraviroc to long-lived carriers. Through targeted synthesis, we discovered an effective linkage site on Maraviroc and demonstrate the potential of these derivatives to prepare potent chemically programmed antibodies and PEGylated derivatives. The resulting compounds effectively neutralized a variety of HIV-1 isolates. Both chemically programmed antibody and PEGylation approaches extend the neutralization activity of serum circulating Maraviroc. Derivation of a successful conjugation strategy for Maraviroc should further enable its use in chemically programmed vaccines, novel bispecific antibodies, and topical microbicides.
|
Antagonist activity against CCR5 receptor in human TZM-bl cells assessed as inhibition of HIV-1 JR-FL-induced cell-cell fusion between viral envelope protein expressing human HEK293 cells to TZM-bl cells after 48 hrs by luciferase reporter gene assay
|
Homo sapiens
|
1.6
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Preparation and activities of macromolecule conjugates of the CCR5 antagonist Maraviroc.
Year : 2014
Volume : 5
Issue : 2
First Page : 133
Last Page : 137
Authors : Asano S, Gavrilyuk J, Burton DR, Barbas CF.
Abstract : CCR5 antagonists are among the most advanced approaches in HIV therapy and may also be relevant to treatment of graft-versus-host disease and Staphylococcus aureus infection. To expand the potential of the only approved CCR5 antagonist, Maraviroc, we studied derivatives that would enable functional linkage of Maraviroc to long-lived carriers. Through targeted synthesis, we discovered an effective linkage site on Maraviroc and demonstrate the potential of these derivatives to prepare potent chemically programmed antibodies and PEGylated derivatives. The resulting compounds effectively neutralized a variety of HIV-1 isolates. Both chemically programmed antibody and PEGylation approaches extend the neutralization activity of serum circulating Maraviroc. Derivation of a successful conjugation strategy for Maraviroc should further enable its use in chemically programmed vaccines, novel bispecific antibodies, and topical microbicides.
|
Antagonist activity against CCR5 receptor in human TZM-bl cells assessed as inhibition of HIV-1 YU2-induced cell-cell fusion between viral envelope protein expressing human HEK293 cells to TZM-bl cells after 48 hrs by luciferase reporter gene assay
|
Homo sapiens
|
0.43
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Preparation and activities of macromolecule conjugates of the CCR5 antagonist Maraviroc.
Year : 2014
Volume : 5
Issue : 2
First Page : 133
Last Page : 137
Authors : Asano S, Gavrilyuk J, Burton DR, Barbas CF.
Abstract : CCR5 antagonists are among the most advanced approaches in HIV therapy and may also be relevant to treatment of graft-versus-host disease and Staphylococcus aureus infection. To expand the potential of the only approved CCR5 antagonist, Maraviroc, we studied derivatives that would enable functional linkage of Maraviroc to long-lived carriers. Through targeted synthesis, we discovered an effective linkage site on Maraviroc and demonstrate the potential of these derivatives to prepare potent chemically programmed antibodies and PEGylated derivatives. The resulting compounds effectively neutralized a variety of HIV-1 isolates. Both chemically programmed antibody and PEGylation approaches extend the neutralization activity of serum circulating Maraviroc. Derivation of a successful conjugation strategy for Maraviroc should further enable its use in chemically programmed vaccines, novel bispecific antibodies, and topical microbicides.
|
Antagonist activity at CCR5 in Gqi5 transfected human MOLT4 cells assessed as inhibition of RANTES-stimulated Ca2+ influx preincubated for 15 mins followed by DAMGO challenge
|
Homo sapiens
|
2.2
nM
|
|
Journal : MedChemComm
Title : A Bivalent Ligand Targeting the Putative Mu Opioid Receptor and Chemokine Receptor CCR5 Heterodimers: Binding Affinity versus Functional Activities.
Year : 2013
Volume : 4
Issue : 5
First Page : 847
Last Page : 851
Authors : Yuan Y, Arnatt CK, El-Hage N, Dever SM, Jacob JC, Selley DE, Hauser KF, Zhang Y.
Abstract : Opioid substitution and antiretroviral therapies have steadily increased the life spans of AIDS patients with opioid addiction, while the adverse drug-drug interactions and persistence of HIV-associated neurocognitive disorders still require new strategies to target opioid abuse and HIV-1 comorbidities. A bivalent ligand 1 with a 21-atom spacer was thus synthesized and explicitly characterized as a novel pharmacological probe to study the underlying mechanism of opioid-enhanced NeuroAIDS. The steric hindrance generated from the spacer affected the binding affinity and Ca(2+) flux inhibition function activity of bivalent ligand 1 at the chemokine receptor CCR5 more profoundly than it did at the mu opioid receptor (MOR). However, the CCR5 radioligand binding affinity and the Ca(2+) flux inhibition function of the ligand seemed not necessarily to correlate with its antiviral activity given that it was at least two times more potent than maraviroc alone in reducing Tat expression upon HIV-1 infection in human astrocytes. Furthermore, the ligand was also about two times more potent than the simple mixture of maraviroc and naltrexone in the same viral entry inhibition assay. Therefore bivalent ligand 1 seemed to function more effectively by targeting specifically the putative MOR-CCR5 heterodimer in the viral invasion process. The results reported here suggest that a properly designed bivalent ligand may serve as a useful chemical probe to study the potential MOR-CCR5 interaction during the progression of NeuroAIDS.
|
Displacement of [125I]-MIP-1alpha from CCR5 in rhesus monkey Chem-1 cell membranes after 120 mins by liquid scintillation counting analysis
|
Macaca mulatta
|
0.24
nM
|
|
Journal : MedChemComm
Title : A Bivalent Ligand Targeting the Putative Mu Opioid Receptor and Chemokine Receptor CCR5 Heterodimers: Binding Affinity versus Functional Activities.
Year : 2013
Volume : 4
Issue : 5
First Page : 847
Last Page : 851
Authors : Yuan Y, Arnatt CK, El-Hage N, Dever SM, Jacob JC, Selley DE, Hauser KF, Zhang Y.
Abstract : Opioid substitution and antiretroviral therapies have steadily increased the life spans of AIDS patients with opioid addiction, while the adverse drug-drug interactions and persistence of HIV-associated neurocognitive disorders still require new strategies to target opioid abuse and HIV-1 comorbidities. A bivalent ligand 1 with a 21-atom spacer was thus synthesized and explicitly characterized as a novel pharmacological probe to study the underlying mechanism of opioid-enhanced NeuroAIDS. The steric hindrance generated from the spacer affected the binding affinity and Ca(2+) flux inhibition function activity of bivalent ligand 1 at the chemokine receptor CCR5 more profoundly than it did at the mu opioid receptor (MOR). However, the CCR5 radioligand binding affinity and the Ca(2+) flux inhibition function of the ligand seemed not necessarily to correlate with its antiviral activity given that it was at least two times more potent than maraviroc alone in reducing Tat expression upon HIV-1 infection in human astrocytes. Furthermore, the ligand was also about two times more potent than the simple mixture of maraviroc and naltrexone in the same viral entry inhibition assay. Therefore bivalent ligand 1 seemed to function more effectively by targeting specifically the putative MOR-CCR5 heterodimer in the viral invasion process. The results reported here suggest that a properly designed bivalent ligand may serve as a useful chemical probe to study the potential MOR-CCR5 interaction during the progression of NeuroAIDS.
|
Antagonist activity against CCR5 (unknown origin) expressed in CHO cells co-expressing Galpha16 incubated for 10 mins assessed as inhibition of RANTES-induced calcium mobilization
|
Homo sapiens
|
13.1
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of novel 2-methylpiperazine derivatives as potent CCR5 antagonists.
Year : 2015
Volume : 23
Issue : 5
First Page : 1157
Last Page : 1168
Authors : Hu S, Wang Z, Hou T, Ma X, Li J, Liu T, Xie X, Hu Y.
Abstract : Three series of novel 2-methylpiperazine derivatives were designed and synthesized using a fragment-assembly strategy. Among them, six compounds (13, 16, 18, 22, 33, and 36) showed potent activity against CCR5 comparable to that of the positive control, maraviroc, in calcium mobilization assay. Moreover, some compounds were selected and further tested for their antiviral activity in HIV-1 single cycle assay. As a result, four compounds (13, 16, 33, and 36) showed antiviral activity at the nanomolar level. Additionally, the potent four compounds showed no cytotoxicity at a concentration of 10μM.
|
Antiviral activity against HIV1 infected in human SupT1 cells exposed to supernatant from HIV1 infected human 293T cells incubated for 48 hrs by firefly luciferase assay based single-cycle HIV1 replication assay
|
Human immunodeficiency virus 1
|
5.5
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of novel 2-methylpiperazine derivatives as potent CCR5 antagonists.
Year : 2015
Volume : 23
Issue : 5
First Page : 1157
Last Page : 1168
Authors : Hu S, Wang Z, Hou T, Ma X, Li J, Liu T, Xie X, Hu Y.
Abstract : Three series of novel 2-methylpiperazine derivatives were designed and synthesized using a fragment-assembly strategy. Among them, six compounds (13, 16, 18, 22, 33, and 36) showed potent activity against CCR5 comparable to that of the positive control, maraviroc, in calcium mobilization assay. Moreover, some compounds were selected and further tested for their antiviral activity in HIV-1 single cycle assay. As a result, four compounds (13, 16, 33, and 36) showed antiviral activity at the nanomolar level. Additionally, the potent four compounds showed no cytotoxicity at a concentration of 10μM.
|
Displacement of [125I]-RANTES from CCR5 in mouse NIH/3T3 cells after 1 hr
|
Mus musculus
|
5.2
nM
|
|
Journal : Eur J Med Chem
Title : Recent updates for designing CCR5 antagonists as anti-retroviral agents.
Year : 2018
Volume : 147
First Page : 115
Last Page : 129
Authors : Shah HR, Savjani JK.
Abstract : The healthcare system faces various challenges in human immunodeficiency virus (HIV) therapy due to resistance to Anti-Retroviral Therapy (ART) as a consequence of the evolutionary process. Despite the success of antiretroviral drugs like Zidovudine, Zalcitabine, Raltegravir WHO ranks HIV as one of the deadliest diseases with a mortality of one million lives in 2016. Thus, there emerges an urgency of developing a novel anti-retroviral agent that combat resistant HIV strains. The clinical development of ART from a single drug regimen to current triple drug combination is very slow. The progression in the structural biology of the viral envelope prompted the discovery of novel targets, which can be demonstrated a proficient approach for drug design of anti-retroviral agents. The current review enlightens the recent updates in the structural biology of the viral envelope and focuses on CCR5 as a validated target as well as ways to overcome CCR5 resistance. The article also throws light on the SAR studies and most prevalent mutations in the receptor for designing CCR5 antagonists that can combat HIV-1 infection. To conclude, the paper lists diversified scaffolds that are in pipeline by various pharmaceutical companies that could provide an aid for developing novel CCR5 antagonists.
|
Inhibition of CCR5 in human TZM-bl cells infected with HIV1 Bal R5 assessed as antiviral activity by measuring reduction in viral infection pre-incubated with cells followed by viral infection measured after 3 days by luciferase reporter gene assay
|
Homo sapiens
|
0.2
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of (E)-3,4-dihydroxystyryl 4-acylaminophenethyl sulfone, sulfoxide derivatives as dual inhibitors of HIV-1 CCR5 and integrase.
Year : 2017
Volume : 25
Issue : 3
First Page : 1076
Last Page : 1084
Authors : Sun Y, Xu W, Fan N, Sun X, Ning X, Ma L, Liu J, Wang X.
Abstract : Aiming at the limited effectiveness of current clinical therapeutic effect of AIDS, novel series of compounds bearing (E)-3,4-dihydroxystyryl sulfone (or sulfoxide) and anilide fragments were designed and synthesized as dual inhibitors of HIV-1 CCR5/IN. The biological results indicated that several target compounds showed inhibitory activity against HIV-1 Bal (R5) infection in TZM-bl cells. Besides targeting the chemokine receptor on the host cell surface, they also displayed binding affinities with HIV-1 integrase using the surface plasmon resonance (SPR) binding assays. Molecular docking studies have inferred the possible binding mode of target compounds against integrase. These data demonstrate that the structure of (E)-3,4-dihydroxystyryl sulfone and sulfoxide derivatives have the potential to derive potent dual inhibitors of HIV-1 Integrase and CCR5.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
7.65
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
23.65
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.02
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.07
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.07
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.02
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Antagonist activity at human CCR5 receptor expressed in HEK293 cells co-expressing Galpha15 assessed as inhibition of RNATES-induced intracellular calcium flux measured after 10 mins by FLIPR calcium mobilization assay
|
Homo sapiens
|
0.82
nM
|
|
