|
Evaluated for the anti-HIV activity against HIV-1 replication in H9 lymphocyte cells
|
Homo sapiens
|
0.35
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3,28-Di-O-(dimethylsuccinyl)-betulin isomers as anti-HIV agents.
Year : 2001
Volume : 11
Issue : 2
First Page : 183
Last Page : 185
Authors : Kashiwada Y, Chiyo J, Ikeshiro Y, Nagao T, Okabe H, Cosentino LM, Fowke K, Lee KH.
Abstract : Four isomers of 3,28-di-O-(dimethylsuccinyl)-betulin were prepared and evaluated for anti-HIV activity against HIV-1 replication in H9 lymphocyte cells. 3-O-(3',3'-Dimethylsuccinyl)-28-O-(2", 2"-dimethvlsuccinyl)-betulin (11) was the most potent anti-HIV compound with an EC5, value of 0.00087 microM and a TI value of 42,400.
|
Anti-HIV activity against acutely infected H9 lymphocytes. Activity expressed as concentration of compound able to suppress HIV replication by 50%.
|
None
|
0.35
nM
|
|
Journal : J. Med. Chem.
Title : Anti-AIDS agents. 34. Synthesis and structure-activity relationships of betulin derivatives as anti-HIV agents.
Year : 1998
Volume : 41
Issue : 23
First Page : 4648
Last Page : 4657
Authors : Sun IC, Wang HK, Kashiwada Y, Shen JK, Cosentino LM, Chen CH, Yang LM, Lee KH.
Abstract : Succinyl and 3'-substituted glutaryl betulin derivatives showed stronger anti-HIV activity and higher therapeutic index (TI) values than their dihydrobetulin counterparts, with ratios of 1.2:1 to 15:1 (cf. 7 and 15, 9 and 17, 10 and 18, 11 and 19, and 12 and 20). For various 3'-substituted glutaryl compounds, the order of anti-HIV effects, from strong to weak inhibition, was 3',3'-dimethyl, 3'-methyl, 3'-ethyl-3'-methyl, followed by 3',3'-tetramethylene glutaryl derivatives (10 > 9 > 11 > 12, 18 > 17 > 19 > 20). The most potent compound, 10, has two 3',3'-dimethylglutaryl groups and displays significant anti-HIV potency with an EC50 value of 0.000 66 microM and a TI of 21 515. Results for compounds (22 and 23) without a C-3 acyl group confirmed the importance of the C-3 acyl group to the anti-HIV effect. With 3',3'-tetramethylene glutaryl derivatives, triacyl 29 showed stronger inhibition than diacyl 12; in contrast, 3',3'-dimethylglutaryl compounds displayed opposite results. 3-Keto compounds (35 and 36) and 2,3-dihydro compounds (39 and 40) had EC50 values in the range of 4.3-10.0 microM, suggesting that A ring modification led to decreased potency. The reduced activity of amide (33 and 34), ester (41), and oxime (42) analogues suggested that the orientation and linkage of the C-3 acyl side chain play crucial roles in the potent anti-HIV activity. Finally, replacing the C-28 acyl group with a bulky non-carboxylic group produced a less potent compound (44). In the study of mechanism of action, our results indicated that fusion is not the primary target for the anti-HIV activity of 10. It appears to inhibit HIV replication at a late stage of the viral life cycle, i.e., after viral protein synthesis.
|
Concentration required to inhibit 50% of HIV-1 (human immunodeficiency virus-1) replication
|
Human immunodeficiency virus 1
|
0.35
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3-O-Glutaryl-dihydrobetulin and related monoacyl derivatives as potent anti-HIV agents.
Year : 2004
Volume : 14
Issue : 23
First Page : 5851
Last Page : 5853
Authors : Kashiwada Y, Sekiya M, Ikeshiro Y, Fujioka T, Kilgore NR, Wild CT, Allaway GP, Lee KH.
Abstract : 3-O-Acyl-betulin and -dihydrobetulin derivatives were prepared and evaluated for anti-HIV activity. 3-O-Glutaryl-dihydrobetulin (17) demonstrated extremely potent anti-HIV activity with an EC(50) value of 2 x 10(-5) microM and a TI value of 1.12 x 10(6). 3-O-(3',3'-Dimethylsuccinyl)- and 3-O-(3',3'-dimethylglutaryl)-dihydrobetulins (15, 16) were also potent anti-HIV compounds with EC(50) values of 0.0017 and 0.0013 microM, respectively, and TI values of 16,160 and 19,530, respectively.
|
Antiviral activity against HIV1 3B in H9 lymphocytes
|
None
|
7.0
nM
|
|
Journal : J. Med. Chem.
Title : Anti-AIDS agents 69. Moronic acid and other triterpene derivatives as novel potent anti-HIV agents.
Year : 2006
Volume : 49
Issue : 18
First Page : 5462
Last Page : 5469
Authors : Yu D, Sakurai Y, Chen CH, Chang FR, Huang L, Kashiwada Y, Lee KH.
Abstract : In a continuing structure-activity relationship study of potent anti-HIV agents, seven new triterpene derivatives were designed, synthesized, and evaluated for in vitro antiviral activity. Among them, moronic acid derivatives 19, 20, and 21 showed significant activity in HIV-1 infected H9 lymphocytes. Compounds 19 and 20 were also evaluated against HIV-1 NL4-3 and drug resistant strains in the MT-4 cell line. Compounds 19 and 20 showed better antiviral profiles than the betulinic acid analogue 8 (PA-457), which has successfully completed a Phase IIa clinical trial. Compound 20 showed potent anti-HIV activity with EC50 values of 0.0085 microM against NL4-3, 0.021 microM against PI-R (a multiple protease inhibitor resistant strain), and 0.13 microM against FHR-2 (an HIV strain resistant to 8). Promising compound 20 has become a new lead for modification, and further development of 20-related compounds as clinical trial candidates is warranted.
|
Antiviral activity against HIV1 NL4-3 in MT4 cells
|
None
|
96.0
nM
|
|
Journal : J. Med. Chem.
Title : Anti-AIDS agents 69. Moronic acid and other triterpene derivatives as novel potent anti-HIV agents.
Year : 2006
Volume : 49
Issue : 18
First Page : 5462
Last Page : 5469
Authors : Yu D, Sakurai Y, Chen CH, Chang FR, Huang L, Kashiwada Y, Lee KH.
Abstract : In a continuing structure-activity relationship study of potent anti-HIV agents, seven new triterpene derivatives were designed, synthesized, and evaluated for in vitro antiviral activity. Among them, moronic acid derivatives 19, 20, and 21 showed significant activity in HIV-1 infected H9 lymphocytes. Compounds 19 and 20 were also evaluated against HIV-1 NL4-3 and drug resistant strains in the MT-4 cell line. Compounds 19 and 20 showed better antiviral profiles than the betulinic acid analogue 8 (PA-457), which has successfully completed a Phase IIa clinical trial. Compound 20 showed potent anti-HIV activity with EC50 values of 0.0085 microM against NL4-3, 0.021 microM against PI-R (a multiple protease inhibitor resistant strain), and 0.13 microM against FHR-2 (an HIV strain resistant to 8). Promising compound 20 has become a new lead for modification, and further development of 20-related compounds as clinical trial candidates is warranted.
|
Antiviral activity against HIV1 NL4-3 replication in human MT4 cells
|
None
|
96.0
nM
|
|
Journal : J. Med. Chem.
Title : Anti-AIDS agents 69. Moronic acid and other triterpene derivatives as novel potent anti-HIV agents.
Year : 2006
Volume : 49
Issue : 18
First Page : 5462
Last Page : 5469
Authors : Yu D, Sakurai Y, Chen CH, Chang FR, Huang L, Kashiwada Y, Lee KH.
Abstract : In a continuing structure-activity relationship study of potent anti-HIV agents, seven new triterpene derivatives were designed, synthesized, and evaluated for in vitro antiviral activity. Among them, moronic acid derivatives 19, 20, and 21 showed significant activity in HIV-1 infected H9 lymphocytes. Compounds 19 and 20 were also evaluated against HIV-1 NL4-3 and drug resistant strains in the MT-4 cell line. Compounds 19 and 20 showed better antiviral profiles than the betulinic acid analogue 8 (PA-457), which has successfully completed a Phase IIa clinical trial. Compound 20 showed potent anti-HIV activity with EC50 values of 0.0085 microM against NL4-3, 0.021 microM against PI-R (a multiple protease inhibitor resistant strain), and 0.13 microM against FHR-2 (an HIV strain resistant to 8). Promising compound 20 has become a new lead for modification, and further development of 20-related compounds as clinical trial candidates is warranted.
|
Antiviral activity against HIV1 PI-R replication in human MT4 cells
|
None
|
430.0
nM
|
|
Journal : J. Med. Chem.
Title : Anti-AIDS agents 69. Moronic acid and other triterpene derivatives as novel potent anti-HIV agents.
Year : 2006
Volume : 49
Issue : 18
First Page : 5462
Last Page : 5469
Authors : Yu D, Sakurai Y, Chen CH, Chang FR, Huang L, Kashiwada Y, Lee KH.
Abstract : In a continuing structure-activity relationship study of potent anti-HIV agents, seven new triterpene derivatives were designed, synthesized, and evaluated for in vitro antiviral activity. Among them, moronic acid derivatives 19, 20, and 21 showed significant activity in HIV-1 infected H9 lymphocytes. Compounds 19 and 20 were also evaluated against HIV-1 NL4-3 and drug resistant strains in the MT-4 cell line. Compounds 19 and 20 showed better antiviral profiles than the betulinic acid analogue 8 (PA-457), which has successfully completed a Phase IIa clinical trial. Compound 20 showed potent anti-HIV activity with EC50 values of 0.0085 microM against NL4-3, 0.021 microM against PI-R (a multiple protease inhibitor resistant strain), and 0.13 microM against FHR-2 (an HIV strain resistant to 8). Promising compound 20 has become a new lead for modification, and further development of 20-related compounds as clinical trial candidates is warranted.
|
Antiviral activity against HIV1
|
Human immunodeficiency virus 1
|
1.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Anti-AIDS agents 73: structure-activity relationship study and asymmetric synthesis of 3-O-monomethylsuccinyl-betulinic acid derivatives.
Year : 2007
Volume : 17
Issue : 23
First Page : 6553
Last Page : 6557
Authors : Qian K, Nakagawa-Goto K, Yu D, Morris-Natschke SL, Nitz TJ, Kilgore N, Allaway GP, Lee KH.
Abstract : 3-O-3'(or 2')-Methylsuccinyl-betulinic acid (MSB) derivatives were separated by using recycle HPLC. The structures of four isomers were assigned by NMR and asymmetric synthesis. 3-O-3'S-Methylsuccinyl-betulinic acid (3'S-MSB, 4) exhibited potent anti-HIV activity with an EC(50) value of 0.0087microM and a TI value of 6.3x10(3), which is comparable to the data for bevirimat (DSB, PA-457), a current clinical trials drug that was also derived from betulinic acid. The anti-HIV potency of 4 was slightly better than that of AZT.
|
Antiviral activity against HIV1 3B infected in human MT2 cells assessed as p24 antigen level after 4 days by ELISA
|
Human immunodeficiency virus 1
|
11.0
nM
|
|
Journal : J. Med. Chem.
Title : Anti-AIDS agents. 78. Design, synthesis, metabolic stability assessment, and antiviral evaluation of novel betulinic acid derivatives as potent anti-human immunodeficiency virus (HIV) agents.
Year : 2009
Volume : 52
Issue : 10
First Page : 3248
Last Page : 3258
Authors : Qian K, Yu D, Chen CH, Huang L, Morris-Natschke SL, Nitz TJ, Salzwedel K, Reddick M, Allaway GP, Lee KH.
Abstract : In a continuing study of potent anti-HIV agents, seventeen 28,30-disubstituted betulinic acid (BA, 1) derivatives and seven novel 3,28-disubstituted BA analogues were designed, synthesized, and evaluated for in vitro antiviral activity. Among them, compound 21 showed an improved solubility and equal anti-HIV potency (EC(50) = 0.09 microM) when compared to HIV entry inhibitors 3b (IC9564, (3R,4S)-N'-[N-[3beta-hydroxy-lup-20(29)-en-28-oyl]-8-aminooctanoyl]-4-amino-3-hydroxy-6-methylheptanoic acid) and 4 (A43-D, [[N-[3beta-O-(3',3'-dimethylsuccinyl)-lup-20(29)-en-28-oyl]-7-aminoheptyl]carbamoyl]methane). Using a cyclic secondary amine to form the C-28 amide bond increased the metabolic stability of the derivatives significantly in pooled human liver microsomes. The most potent compounds 47 and 48 displayed potent anti-HIV activity with EC(50) values of 0.007 and 0.006 microM, respectively. These results are slightly better than that of bevirimat (2, 3',3'-dimethylsuccinylbetulinic acid), which is currently in phase IIb clinical trials. Compounds 47 and 48 should serve as attractive promising leads to develop next generation, metabolically stable, 3,28-disubstituted bifunctional HIV-1 inhibitors as clinical trials candidates.
|
Antiviral activity against HIV1 assessed as inhibition of release of CA/p24 from CA-SP1/p25 at 37.8 nM by MAGI assay
|
Human immunodeficiency virus 1
|
90.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Phase I and II study of the safety, virologic effect, and pharmacokinetics/pharmacodynamics of single-dose 3-o-(3',3'-dimethylsuccinyl)betulinic acid (bevirimat) against human immunodeficiency virus infection.
Year : 2007
Volume : 51
Issue : 10
First Page : 3574
Last Page : 3581
Authors : Smith PF, Ogundele A, Forrest A, Wilton J, Salzwedel K, Doto J, Allaway GP, Martin DE.
Abstract : Bevirimat [3-O-(3',3'-dimethylsuccinyl)betulinic acid] is the first in a new class of anti-human immunodeficiency virus (HIV) drugs that inhibit viral maturation by specifically blocking cleavage of the Gag capsid (CA) precursor, CA-SP1, to mature CA protein, resulting in defective core condensation and release of immature noninfectious virions. Four cohorts of six HIV-infected adults, with CD4 counts of >200 and plasma viral loads of 5,000 to 250,000 transcripts/ml and not currently receiving antiretroviral therapy, were randomized to receive a single oral dose of placebo, 75, 150, or 250 mg of bevirimat. Thirty blood samples for drug concentrations and 20 HIV RNA measures were collected from each subject over a 20-day period. Candidate pharmacokinetic/pharmacodynamic models were fit to individual subjects by maximum likelihood followed by Bayesian estimation; model discrimination was by corrected Akaike's Information Criterion. The bevirimat pharmacokinetics was well described by an oral two-compartment linear model (r(2), 0.98), with a mean (percent coefficient of variation) half-life of 60.3 (13.6) h and apparent oral clearance of bevirimat from the plasma compartment of 0.17 (18) liters/h. HIV RNA was modeled as being produced in infected CD4 cells, with bevirimat inhibiting infection of new CD4 cells thru a Hill-type function (r(2), 0.87). Single oral doses of bevirimat were well tolerated and demonstrated a dose-dependent reduction in viral load. The average maximum reduction from baseline following the 150- and 250-mg doses was greater than 0.45 log(10), with individual patients having reductions of greater than 0.7 log(10). No bevirimat resistance mutations were detected during the course of the study.
|
Antiviral activity against HIV1 infected in human assessed as inhibition of viral replication at 75 mg, po
|
Human immunodeficiency virus 1
|
0.00119
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Phase I and II study of the safety, virologic effect, and pharmacokinetics/pharmacodynamics of single-dose 3-o-(3',3'-dimethylsuccinyl)betulinic acid (bevirimat) against human immunodeficiency virus infection.
Year : 2007
Volume : 51
Issue : 10
First Page : 3574
Last Page : 3581
Authors : Smith PF, Ogundele A, Forrest A, Wilton J, Salzwedel K, Doto J, Allaway GP, Martin DE.
Abstract : Bevirimat [3-O-(3',3'-dimethylsuccinyl)betulinic acid] is the first in a new class of anti-human immunodeficiency virus (HIV) drugs that inhibit viral maturation by specifically blocking cleavage of the Gag capsid (CA) precursor, CA-SP1, to mature CA protein, resulting in defective core condensation and release of immature noninfectious virions. Four cohorts of six HIV-infected adults, with CD4 counts of >200 and plasma viral loads of 5,000 to 250,000 transcripts/ml and not currently receiving antiretroviral therapy, were randomized to receive a single oral dose of placebo, 75, 150, or 250 mg of bevirimat. Thirty blood samples for drug concentrations and 20 HIV RNA measures were collected from each subject over a 20-day period. Candidate pharmacokinetic/pharmacodynamic models were fit to individual subjects by maximum likelihood followed by Bayesian estimation; model discrimination was by corrected Akaike's Information Criterion. The bevirimat pharmacokinetics was well described by an oral two-compartment linear model (r(2), 0.98), with a mean (percent coefficient of variation) half-life of 60.3 (13.6) h and apparent oral clearance of bevirimat from the plasma compartment of 0.17 (18) liters/h. HIV RNA was modeled as being produced in infected CD4 cells, with bevirimat inhibiting infection of new CD4 cells thru a Hill-type function (r(2), 0.87). Single oral doses of bevirimat were well tolerated and demonstrated a dose-dependent reduction in viral load. The average maximum reduction from baseline following the 150- and 250-mg doses was greater than 0.45 log(10), with individual patients having reductions of greater than 0.7 log(10). No bevirimat resistance mutations were detected during the course of the study.
|
Antiviral activity against HIV1 infected in human assessed as inhibition of viral replication at 150 mg, po
|
Human immunodeficiency virus 1
|
0.00035
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Phase I and II study of the safety, virologic effect, and pharmacokinetics/pharmacodynamics of single-dose 3-o-(3',3'-dimethylsuccinyl)betulinic acid (bevirimat) against human immunodeficiency virus infection.
Year : 2007
Volume : 51
Issue : 10
First Page : 3574
Last Page : 3581
Authors : Smith PF, Ogundele A, Forrest A, Wilton J, Salzwedel K, Doto J, Allaway GP, Martin DE.
Abstract : Bevirimat [3-O-(3',3'-dimethylsuccinyl)betulinic acid] is the first in a new class of anti-human immunodeficiency virus (HIV) drugs that inhibit viral maturation by specifically blocking cleavage of the Gag capsid (CA) precursor, CA-SP1, to mature CA protein, resulting in defective core condensation and release of immature noninfectious virions. Four cohorts of six HIV-infected adults, with CD4 counts of >200 and plasma viral loads of 5,000 to 250,000 transcripts/ml and not currently receiving antiretroviral therapy, were randomized to receive a single oral dose of placebo, 75, 150, or 250 mg of bevirimat. Thirty blood samples for drug concentrations and 20 HIV RNA measures were collected from each subject over a 20-day period. Candidate pharmacokinetic/pharmacodynamic models were fit to individual subjects by maximum likelihood followed by Bayesian estimation; model discrimination was by corrected Akaike's Information Criterion. The bevirimat pharmacokinetics was well described by an oral two-compartment linear model (r(2), 0.98), with a mean (percent coefficient of variation) half-life of 60.3 (13.6) h and apparent oral clearance of bevirimat from the plasma compartment of 0.17 (18) liters/h. HIV RNA was modeled as being produced in infected CD4 cells, with bevirimat inhibiting infection of new CD4 cells thru a Hill-type function (r(2), 0.87). Single oral doses of bevirimat were well tolerated and demonstrated a dose-dependent reduction in viral load. The average maximum reduction from baseline following the 150- and 250-mg doses was greater than 0.45 log(10), with individual patients having reductions of greater than 0.7 log(10). No bevirimat resistance mutations were detected during the course of the study.
|
Antiviral activity against HIV1 infected in human assessed as inhibition of viral replication at 250 mg, po
|
Human immunodeficiency virus 1
|
0.00055
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Phase I and II study of the safety, virologic effect, and pharmacokinetics/pharmacodynamics of single-dose 3-o-(3',3'-dimethylsuccinyl)betulinic acid (bevirimat) against human immunodeficiency virus infection.
Year : 2007
Volume : 51
Issue : 10
First Page : 3574
Last Page : 3581
Authors : Smith PF, Ogundele A, Forrest A, Wilton J, Salzwedel K, Doto J, Allaway GP, Martin DE.
Abstract : Bevirimat [3-O-(3',3'-dimethylsuccinyl)betulinic acid] is the first in a new class of anti-human immunodeficiency virus (HIV) drugs that inhibit viral maturation by specifically blocking cleavage of the Gag capsid (CA) precursor, CA-SP1, to mature CA protein, resulting in defective core condensation and release of immature noninfectious virions. Four cohorts of six HIV-infected adults, with CD4 counts of >200 and plasma viral loads of 5,000 to 250,000 transcripts/ml and not currently receiving antiretroviral therapy, were randomized to receive a single oral dose of placebo, 75, 150, or 250 mg of bevirimat. Thirty blood samples for drug concentrations and 20 HIV RNA measures were collected from each subject over a 20-day period. Candidate pharmacokinetic/pharmacodynamic models were fit to individual subjects by maximum likelihood followed by Bayesian estimation; model discrimination was by corrected Akaike's Information Criterion. The bevirimat pharmacokinetics was well described by an oral two-compartment linear model (r(2), 0.98), with a mean (percent coefficient of variation) half-life of 60.3 (13.6) h and apparent oral clearance of bevirimat from the plasma compartment of 0.17 (18) liters/h. HIV RNA was modeled as being produced in infected CD4 cells, with bevirimat inhibiting infection of new CD4 cells thru a Hill-type function (r(2), 0.87). Single oral doses of bevirimat were well tolerated and demonstrated a dose-dependent reduction in viral load. The average maximum reduction from baseline following the 150- and 250-mg doses was greater than 0.45 log(10), with individual patients having reductions of greater than 0.7 log(10). No bevirimat resistance mutations were detected during the course of the study.
|
Inhibition of TPA-induced EBV-early antigen activation in human Raji cells assessed as EA induction after 48 hrs relative to TPA
|
Human herpesvirus 4
|
396.0
molar ratio
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cancer preventive agents 9. Betulinic acid derivatives as potent cancer chemopreventive agents.
Year : 2009
Volume : 19
Issue : 13
First Page : 3378
Last Page : 3381
Authors : Nakagawa-Goto K, Yamada K, Taniguchi M, Tokuda H, Lee KH.
Abstract : C-3 esterifications of betulinic acid (BA, 1) and its A-ring homolog, ceanothic acid (CA, 2), were carried out to provide sixteen terpenoids, 4-19, including nine new compounds (4-12). All synthesized compounds were evaluated in an in vitro antitumor-promoting assay using the Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. Among them, compounds 4-6, 11-14, 16, and 17 displayed remarkable inhibitory effects of EBV-EA activation. BA analog 6, which contains a prenyl-like group, showed the most potent inhibitory effect (100%, 76%, 37%, and 11% inhibition of EBA activation at 1000, 500, 100, and 10mol ratio/TPA, respectively, with IC(50) value of 285mol ratio/32pmol TPA). Compound 6 merits further development as a cancer preventive agent.
|
Cytotoxicity against mock-infected human H9 cells
|
Homo sapiens
|
0.35
nM
|
|
Journal : J. Nat. Prod.
Title : Anti-AIDS agents 38. Anti-HIV activity of 3-O-acyl ursolic acid derivatives.
Year : 2000
Volume : 63
Issue : 12
First Page : 1619
Last Page : 1622
Authors : Kashiwada Y, Nagao T, Hashimoto A, Ikeshiro Y, Okabe H, Cosentino LM, Lee KH.
Abstract : Based on our previous finding that 3-O-acyl-betulinic and -oleanolic acids, especially the 3-O-(3',3'-dimethyl)-succinyl derivatives (2 and 4), demonstrated potent anti-HIV activity [EC(50) < 0.00035 and 0.00086 microM; therapeutic index (TI) > 20 000 and 22 326, respectively], several 3-O-acyl-ursolic acids were prepared and evaluated for anti-HIV activity. Ursolic acid (6) was equipotent (EC(50) 4.4 microM) with oleanolic acid (EC(50) 3.7 microM), although it was slightly toxic (IC(50) 14.3 microM, TI 3.3). 3-O-Diglycoryl-ursolic acid (10) demonstrated relatively potent anti-HIV activity with an EC(50) of 0. 31 microM and a TI of 155.5. In contrast, 3-O-(3', 3'-dimethylsuccinyl)-ursolic acid (8), which is analogous to the extremely potent anti-HIV betulinic acid and oleanolic acid derivatives 2 and 4, displayed only weak anti-HIV activity (EC(50) 2.1 microM, TI 23.6).
|
Antiviral activity against HIV
|
Human immunodeficiency virus
|
0.35
nM
|
|
Journal : J. Nat. Prod.
Title : Current developments in the discovery and design of new drug candidates from plant natural product leads.
Year : 2004
Volume : 67
Issue : 2
First Page : 273
Last Page : 283
Authors : Lee KH.
Abstract : This review article will emphasize recent research in the Natural Products Laboratory, School of Pharmacy, University of North Carolina at Chapel Hill, on various classes of plant-derived compounds that possess potent antitumor or anti-HIV activity. These compounds were obtained by bioactivity- and mechanism of action-directed isolation and characterization coupled with rational drug design-based modification and analogue synthesis. Structural modification, SAR, and mechanism of action studies are discussed.
|
Antiviral activity against HIV1 NL4-3 infected in human TZM-b1 cells assessed as reduction in luciferase activity after 2 days by luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
130.0
nM
|
|
Journal : J. Med. Chem.
Title : Betulinic acid derivatives as human immunodeficiency virus type 2 (HIV-2) inhibitors.
Year : 2009
Volume : 52
Issue : 23
First Page : 7887
Last Page : 7891
Authors : Dang Z, Lai W, Qian K, Ho P, Lee KH, Chen CH, Huang L.
Abstract : We previously reported that [[N-[3beta-hydroxyllup-20(29)-en-28-oyl]-7-aminoheptyl]carbamoyl]methane (A43D, 4) was a potent HIV-1 entry inhibitor. However, 4 was inactive against HIV-2 virus, suggesting the structural requirements for targeting these two retroviruses are different. In this study, a series of new betulinic acid derivatives were synthesized, and some of them displayed selective anti-HIV-2 activity at nanomolar concentrations. In comparison to compounds with anti-HIV-1 activity, a shorter C-28 side chain is required for optimal anti-HIV-2 activity.
|
Antiviral activity against HIV1 3B infected in human MT2 cells assessed as inhibition of viral replication treated 1 day after infection measured on after 4 days postinfection by p24 antigen ELISA
|
Human immunodeficiency virus 1
|
1.3
nM
|
|
Journal : J. Med. Chem.
Title : Anti-AIDS agents 81. Design, synthesis, and structure-activity relationship study of betulinic acid and moronic acid derivatives as potent HIV maturation inhibitors.
Year : 2010
Volume : 53
Issue : 8
First Page : 3133
Last Page : 3141
Authors : Qian K, Kuo RY, Chen CH, Huang L, Morris-Natschke SL, Lee KH.
Abstract : In our continuing study of triterpene derivatives as potent anti-HIV agents, different C-3 conformationally restricted betulinic acid (BA, 1) derivatives were designed and synthesized in order to explore the conformational space of the C-3 pharmacophore. 3-O-Monomethylsuccinyl-betulinic acid (MSB) analogues were also designed to better understand the contribution of the C-3' dimethyl group of bevirimat (2), the first-in-class HIV maturation inhibitor, which is currently in phase IIb clinical trials. In addition, another triterpene skeleton, moronic acid (MA, 3), was also employed to study the influence of the backbone and the C-3 modification toward the anti-HIV activity of this compound class. This study enabled us to better understand the structure-activity relationships (SAR) of triterpene-derived anti-HIV agents and led to the design and synthesis of compound 12 (EC(50): 0.0006 microM), which displayed slightly better activity than 2 as a HIV-1 maturation inhibitor.
|
Cytotoxicity against human H9 cells after 4 days by coulter counter
|
Homo sapiens
|
0.35
nM
|
|
Journal : J. Nat. Prod.
Title : Discovery and development of natural product-derived chemotherapeutic agents based on a medicinal chemistry approach.
Year : 2010
Volume : 73
Issue : 3
First Page : 500
Last Page : 516
Authors : Lee KH.
Abstract : Medicinal plants have long been an excellent source of pharmaceutical agents. Accordingly, the long-term objectives of the author's research program are to discover and design new chemotherapeutic agents based on plant-derived compound leads by using a medicinal chemistry approach, which is a combination of chemistry and biology. Different examples of promising bioactive natural products and their synthetic analogues, including sesquiterpene lactones, quassinoids, naphthoquinones, phenylquinolones, dithiophenediones, neo-tanshinlactone, tylophorine, suksdorfin, DCK, and DCP, will be presented with respect to their discovery and preclinical development as potential clinical trial candidates. Research approaches include bioactivity- or mechanism of action-directed isolation and characterization of active compounds, rational drug design-based modification and analogue synthesis, and structure-activity relationship and mechanism of action studies. Current clinical trial agents discovered by the Natural Products Research Laboratories, University of North Carolina, include bevirimat (dimethyl succinyl betulinic acid), which is now in phase IIb trials for treating AIDS. Bevirimat is also the first in a new class of HIV drug candidates called "maturation inhibitors". In addition, an etoposide analogue, GL-331, progressed to anticancer phase II clinical trials, and the curcumin analogue JC-9 is in phase II clinical trials for treating acne and in development for trials against prostate cancer. The discovery and development of these clinical trial candidates will also be discussed.
|
Antiviral activity against HIV1 NL4-3 infected in human MT4 cells assessed as inhibition of viral replication after 4 days by p24 antigen based ELISA assay
|
Human immunodeficiency virus 1
|
96.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Conjugates of betulin derivatives with AZT as potent anti-HIV agents.
Year : 2010
Volume : 18
Issue : 17
First Page : 6451
Last Page : 6469
Authors : Xiong J, Kashiwada Y, Chen CH, Qian K, Morris-Natschke SL, Lee KH, Takaishi Y.
Abstract : Fourteen novel conjugates of 3,28-di-O-acylbetulins with AZT were prepared as anti-HIV agents, based on our previously reported potent anti-HIV triterpene leads, including 3-O-acyl and 3,28-di-O-acylbetulins. Nine of the conjugates (49-53, 55, 56, 59, and 60) exhibited potent anti-HIV activity at the submicromolar level, with EC(50) values ranging from 0.040 to 0.098muM in HIV-1(NL4-3) infected MT-4 cells. These compounds were equipotent or more potent than 3-O-(3',3'-dimethylsuccinyl)betulinic acid (2), which is currently in Phase IIb anti-AIDS clinical trial.
|
Antiviral activity against Human immunodeficiency virus 1 LAI infected in human MT-2 cells by XTT-assay
|
Human immunodeficiency virus 1
|
34.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Phenotypic susceptibility to bevirimat in isolates from HIV-1-infected patients without prior exposure to bevirimat.
Year : 2010
Volume : 54
Issue : 6
First Page : 2345
Last Page : 2353
Authors : Margot NA, Gibbs CS, Miller MD.
Abstract : Bevirimat (BVM) is the first of a new class of anti-HIV drugs with a novel mode of action known as maturation inhibitors. BVM inhibits the last cleavage of the Gag polyprotein by HIV-1 protease, leading to the accumulation of the p25 capsid-small peptide 1 (SP1) intermediate and resulting in noninfectious HIV-1 virions. Early clinical studies of BVM showed that over 50% of the patients treated with BVM did not respond to treatment. We investigated the impact of prior antiretroviral (ARV) treatment and/or natural genetic diversity on BVM susceptibility by conducting in vitro phenotypic analyses of viruses made from patient samples. We generated 31 recombinant viruses containing the entire gag and protease genes from 31 plasma samples from HIV-1-infected patients with (n = 21) or without (n = 10) prior ARV experience. We found that 58% of the patient isolates tested had a >10-fold reduced susceptibility to BVM, regardless of the patient's ARV experience or the level of isolate resistance to protease inhibitors. Analysis of mutants with site-directed mutations confirmed the role of the V370A SP1 polymorphism (SP1-V7A) in resistance to BVM. Furthermore, we demonstrated for the first time that a capsid polymorphism, V362I (CA protein-V230I), is also a major mutation conferring resistance to BVM. In contrast, none of the previously defined resistance-conferring mutations in Gag selected in vitro (H358Y, L363M, L363F, A364V, A366V, or A366T) were found to occur among the viruses that we analyzed. Our results should be helpful in the design of diagnostics for prediction of the potential benefit of BVM treatment in HIV-1-infected patients.
|
Antiviral activity against Human immunodeficiency virus 1 NL4-3 infected in MT4 lymphocytes assessed as p24 antigen level by ELISA
|
Human immunodeficiency virus 1
|
82.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Efficient synthesis and biological evaluation of epiceanothic acid and related compounds.
Year : 2011
Volume : 21
Issue : 1
First Page : 338
Last Page : 341
Authors : Zhang P, Xu L, Qian K, Liu J, Zhang L, Lee KH, Sun H.
Abstract : Epiceanothic acid (1) is a naturally occurring, but very rare pentacyclic triterpene with a unique pentacyclic triterpene (PT) structure. An efficient synthesis of 1 starting from betulin (3) has been accomplished in 12-steps with a total yield of 10% in our study. Compound 1 and selected synthetic intermediates were further evaluated as anti-HIV-1 agents, inhibitors of glycogen phosphorylase (GP), and cytotoxic agents. Compound 1 exhibited moderate HIV-1 inhibition. Most importantly, compound 5, with an opened A-ring, showed significant GP inhibitory activity with an IC(50) of 0.21 μM, suggesting a potential for development as an anti-diabetic agent. On the other hand, compound 12, with a closed A-ring, showed potent cytotoxicity against A549 and MCF-7 human tumor cell lines, with IC(50) values of 0.89 and 0.33 μM, respectively. These results suggest that the A-ring of PTs is an important pharmacophore that could be modified to involve different biological activities.
|
Antiviral activity against HIV1 clinical isolates
|
Human immunodeficiency virus 1
|
10.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Susceptibility of human immunodeficiency virus type 1 to the maturation inhibitor bevirimat is modulated by baseline polymorphisms in Gag spacer peptide 1.
Year : 2009
Volume : 53
Issue : 5
First Page : 2185
Last Page : 2188
Authors : Van Baelen K, Salzwedel K, Rondelez E, Van Eygen V, De Vos S, Verheyen A, Steegen K, Verlinden Y, Allaway GP, Stuyver LJ.
Abstract : In this study, we evaluated baseline susceptibility to bevirimat (BVM), the first in a new class of antiretroviral agents, maturation inhibitors. We evaluated susceptibility to BVM by complete gag genotypic and phenotypic testing of 20 patient-derived human immunodeficiency virus type 1 isolates and 20 site-directed mutants. We found that reduced BVM susceptibility was associated with naturally occurring polymorphisms at positions 6, 7, and 8 in Gag spacer peptide 1.
|
Antiviral activity against wild type HIV1 infected in human HeLa cells assessed as decrease in viral infection after 72 hrs by beta-galactosidase reporter gene assay
|
Human immunodeficiency virus 1
|
9.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : New small-molecule inhibitor class targeting human immunodeficiency virus type 1 virion maturation.
Year : 2009
Volume : 53
Issue : 12
First Page : 5080
Last Page : 5087
Authors : Blair WS, Cao J, Fok-Seang J, Griffin P, Isaacson J, Jackson RL, Murray E, Patick AK, Peng Q, Perros M, Pickford C, Wu H, Butler SL.
Abstract : A new small-molecule inhibitor class that targets virion maturation was identified from a human immunodeficiency virus type 1 (HIV-1) antiviral screen. PF-46396, a representative molecule, exhibits antiviral activity against HIV-1 laboratory strains and clinical isolates in T-cell lines and peripheral blood mononuclear cells (PBMCs). PF-46396 specifically inhibits the processing of capsid (CA)/spacer peptide 1 (SP1) (p25), resulting in the accumulation of CA/SP1 (p25) precursor proteins and blocked maturation of the viral core particle. Viral variants resistant to PF-46396 contain a single amino acid substitution in HIV-1 CA sequences (CAI201V), distal to the CA/SP1 cleavage site in the primary structure, which we demonstrate is sufficient to confer significant resistance to PF-46396 and 3-O-(3',3'-dimethylsuccinyl) betulinic acid (DSB), a previously described maturation inhibitor. Conversely, a single amino substitution in SP1 (SP1A1V), which was previously associated with DSB in vitro resistance, was sufficient to confer resistance to DSB and PF-46396. Further, the CAI201V substitution restored CA/SP1 processing in HIV-1-infected cells treated with PF-46396 or DSB. Our results demonstrate that PF-46396 acts through a mechanism that is similar to DSB to inhibit the maturation of HIV-1 virions. To our knowledge, PF-46396 represents the first small-molecule HIV-1 maturation inhibitor that is distinct in chemical class from betulinic acid-derived maturation inhibitors (e.g., DSB), demonstrating that molecules of diverse chemical classes can inhibit this mechanism.
|
Antiviral activity against HIV1 harboring capsid I201V mutant protein infected in human HeLa cells assessed as decrease in viral infection after 72 hrs by beta-galactosidase reporter gene assay
|
Human immunodeficiency virus 1
|
290.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : New small-molecule inhibitor class targeting human immunodeficiency virus type 1 virion maturation.
Year : 2009
Volume : 53
Issue : 12
First Page : 5080
Last Page : 5087
Authors : Blair WS, Cao J, Fok-Seang J, Griffin P, Isaacson J, Jackson RL, Murray E, Patick AK, Peng Q, Perros M, Pickford C, Wu H, Butler SL.
Abstract : A new small-molecule inhibitor class that targets virion maturation was identified from a human immunodeficiency virus type 1 (HIV-1) antiviral screen. PF-46396, a representative molecule, exhibits antiviral activity against HIV-1 laboratory strains and clinical isolates in T-cell lines and peripheral blood mononuclear cells (PBMCs). PF-46396 specifically inhibits the processing of capsid (CA)/spacer peptide 1 (SP1) (p25), resulting in the accumulation of CA/SP1 (p25) precursor proteins and blocked maturation of the viral core particle. Viral variants resistant to PF-46396 contain a single amino acid substitution in HIV-1 CA sequences (CAI201V), distal to the CA/SP1 cleavage site in the primary structure, which we demonstrate is sufficient to confer significant resistance to PF-46396 and 3-O-(3',3'-dimethylsuccinyl) betulinic acid (DSB), a previously described maturation inhibitor. Conversely, a single amino substitution in SP1 (SP1A1V), which was previously associated with DSB in vitro resistance, was sufficient to confer resistance to DSB and PF-46396. Further, the CAI201V substitution restored CA/SP1 processing in HIV-1-infected cells treated with PF-46396 or DSB. Our results demonstrate that PF-46396 acts through a mechanism that is similar to DSB to inhibit the maturation of HIV-1 virions. To our knowledge, PF-46396 represents the first small-molecule HIV-1 maturation inhibitor that is distinct in chemical class from betulinic acid-derived maturation inhibitors (e.g., DSB), demonstrating that molecules of diverse chemical classes can inhibit this mechanism.
|
Antiviral activity against HIV1 NL4-3 infected in human MT2 cells assessed as inhibition of virus-induced cell death at 0.005 multiplicities of infection after 6 days
|
Human immunodeficiency virus 1
|
0.005
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Lersivirine, a nonnucleoside reverse transcriptase inhibitor with activity against drug-resistant human immunodeficiency virus type 1.
Year : 2010
Volume : 54
Issue : 10
First Page : 4451
Last Page : 4463
Authors : Corbau R, Mori J, Phillips C, Fishburn L, Martin A, Mowbray C, Panton W, Smith-Burchnell C, Thornberry A, Ringrose H, Knöchel T, Irving S, Westby M, Wood A, Perros M.
Abstract : The nonnucleoside reverse transcriptase inhibitors (NNRTIs) are key components of highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus type 1 (HIV-1). A major problem with the first approved NNRTIs was the emergence of mutations in the HIV-1 reverse transcriptase (RT), in particular K103N and Y181C, which led to resistance to the entire class. We adopted an iterative strategy to synthesize and test small molecule inhibitors from a chemical series of pyrazoles against wild-type (wt) RT and the most prevalent NNRTI-resistant mutants. The emerging candidate, lersivirine (UK-453,061), binds the RT enzyme in a novel way (resulting in a unique resistance profile), inhibits over 60% of viruses bearing key RT mutations, with 50% effective concentrations (EC(50)s) within 10-fold of those for wt viruses, and has excellent selectivity against a range of human targets. Altogether lersivirine is a highly potent and selective NNRTI, with excellent efficacy against NNRTI-resistant viruses.
|
Antiviral activity against HIV1 NL4-3 infected in human MT2 cells assessed as inhibition of virus-induced cell death at 0.05 multiplicities of infection after 6 days
|
Human immunodeficiency virus 1
|
0.05
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Lersivirine, a nonnucleoside reverse transcriptase inhibitor with activity against drug-resistant human immunodeficiency virus type 1.
Year : 2010
Volume : 54
Issue : 10
First Page : 4451
Last Page : 4463
Authors : Corbau R, Mori J, Phillips C, Fishburn L, Martin A, Mowbray C, Panton W, Smith-Burchnell C, Thornberry A, Ringrose H, Knöchel T, Irving S, Westby M, Wood A, Perros M.
Abstract : The nonnucleoside reverse transcriptase inhibitors (NNRTIs) are key components of highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus type 1 (HIV-1). A major problem with the first approved NNRTIs was the emergence of mutations in the HIV-1 reverse transcriptase (RT), in particular K103N and Y181C, which led to resistance to the entire class. We adopted an iterative strategy to synthesize and test small molecule inhibitors from a chemical series of pyrazoles against wild-type (wt) RT and the most prevalent NNRTI-resistant mutants. The emerging candidate, lersivirine (UK-453,061), binds the RT enzyme in a novel way (resulting in a unique resistance profile), inhibits over 60% of viruses bearing key RT mutations, with 50% effective concentrations (EC(50)s) within 10-fold of those for wt viruses, and has excellent selectivity against a range of human targets. Altogether lersivirine is a highly potent and selective NNRTI, with excellent efficacy against NNRTI-resistant viruses.
|
Antiviral activity against HIV1 NL4-3 infected in human MT2 cells assessed as inhibition of virus-induced cell death at 0.5 multiplicities of infection after 6 days
|
Human immunodeficiency virus 1
|
0.5
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Lersivirine, a nonnucleoside reverse transcriptase inhibitor with activity against drug-resistant human immunodeficiency virus type 1.
Year : 2010
Volume : 54
Issue : 10
First Page : 4451
Last Page : 4463
Authors : Corbau R, Mori J, Phillips C, Fishburn L, Martin A, Mowbray C, Panton W, Smith-Burchnell C, Thornberry A, Ringrose H, Knöchel T, Irving S, Westby M, Wood A, Perros M.
Abstract : The nonnucleoside reverse transcriptase inhibitors (NNRTIs) are key components of highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus type 1 (HIV-1). A major problem with the first approved NNRTIs was the emergence of mutations in the HIV-1 reverse transcriptase (RT), in particular K103N and Y181C, which led to resistance to the entire class. We adopted an iterative strategy to synthesize and test small molecule inhibitors from a chemical series of pyrazoles against wild-type (wt) RT and the most prevalent NNRTI-resistant mutants. The emerging candidate, lersivirine (UK-453,061), binds the RT enzyme in a novel way (resulting in a unique resistance profile), inhibits over 60% of viruses bearing key RT mutations, with 50% effective concentrations (EC(50)s) within 10-fold of those for wt viruses, and has excellent selectivity against a range of human targets. Altogether lersivirine is a highly potent and selective NNRTI, with excellent efficacy against NNRTI-resistant viruses.
|
Antiviral activity against drug-resistant HIV1 isolate
|
Human immunodeficiency virus 1
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New betulinic acid derivatives as potent proteasome inhibitors.
Year : 2011
Volume : 21
Issue : 19
First Page : 5944
Last Page : 5947
Authors : Qian K, Kim SY, Hung HY, Huang L, Chen CH, Lee KH.
Abstract : In this study, 22 new betulinic acid (BA) derivatives were synthesized and tested for their inhibition of the chymotrypsin-like activity of 20S proteasome. From the SAR study, we concluded that the C-3 and C-30 positions are the pharmacophores for increasing the proteasome inhibition effects, and larger lipophilic or aromatic side chains are favored at these positions. Among the BA derivatives tested, compounds 13, 20, and 21 showed the best proteasome inhibition activity with IC(50) values of 1.42, 1.56, and 1.80 μM, respectively, which are three to fourfold more potent than the proteasome inhibition controls LLM-F and lactacystin.
|
Antiviral activity against HIV1
|
Human immunodeficiency virus 1
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New betulinic acid derivatives as potent proteasome inhibitors.
Year : 2011
Volume : 21
Issue : 19
First Page : 5944
Last Page : 5947
Authors : Qian K, Kim SY, Hung HY, Huang L, Chen CH, Lee KH.
Abstract : In this study, 22 new betulinic acid (BA) derivatives were synthesized and tested for their inhibition of the chymotrypsin-like activity of 20S proteasome. From the SAR study, we concluded that the C-3 and C-30 positions are the pharmacophores for increasing the proteasome inhibition effects, and larger lipophilic or aromatic side chains are favored at these positions. Among the BA derivatives tested, compounds 13, 20, and 21 showed the best proteasome inhibition activity with IC(50) values of 1.42, 1.56, and 1.80 μM, respectively, which are three to fourfold more potent than the proteasome inhibition controls LLM-F and lactacystin.
|
Antiviral activity against wild type HIV1 NL4-3 infected in human MT4 cells assessed as reduction of viral p24 level cells by fluorescence assay relative to wild type HIV1 NL4-3 after 4 days by ELISA
|
Human immunodeficiency virus 1
|
76.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of betulinic acid derivatives as entry inhibitors against HIV-1 and bevirimat-resistant HIV-1 variants.
Year : 2012
Volume : 22
Issue : 16
First Page : 5190
Last Page : 5194
Authors : Dang Z, Qian K, Ho P, Zhu L, Lee KH, Huang L, Chen CH.
Abstract : Betulinic acid derivatives modified at the C28 position are HIV-1entry inhibitors such as compound A43D; however, modified at the C3 position instead of C28 give HIV-1 maturation inhibitor such as bevirimat. Bevirimat exhibited promising pharmacokinetic profiles in clinical trials, but its effectiveness was compromised by the high baseline drug resistance of HIV-1 variants with polymorphism in the putative drug binding site. In an effort to determine whether the viruses with bevirimat resistant polymorphism also altered their sensitivities to the betulinic acid derivatives that inhibit HIV-1 entry, a series of new betulinic acid entry inhibitors were synthesized and tested for their activities against HIV-1 NL4-3 and NL4-3 variants resistant to bevirimat. The results show that the bevirimat resistant viruses were approximately 5- to10-fold more sensitive to three new glutamine ester derivatives (13, 15 and 38) and A43D in an HIV-1 multi-cycle replication assay. In contrast, the wild type NL4-3 and the bevirimat resistant variants were equally sensitive to the HIV-1 RT inhibitor AZT. In addition, these three new compounds markedly improved microsomal stability compared to A43D.
|
Antiviral activity against HIV1 NL4-3 infected in human MT4 cells assessed as p24 antigen level after 4 days by ELISA
|
Human immunodeficiency virus 1
|
87.0
nM
|
|
Journal : J. Med. Chem.
Title : Anti-AIDS agents 90. novel C-28 modified bevirimat analogues as potent HIV maturation inhibitors.
Year : 2012
Volume : 55
Issue : 18
First Page : 8128
Last Page : 8136
Authors : Qian K, Bori ID, Chen CH, Huang L, Lee KH.
Abstract : In a continuing study of bevirimat (2), the anti-HIV-maturation clinical trials agent, 28 new betulinic acid (BA, 1) derivatives were designed and synthesized. Among these compounds, 17, with a C-28 MEM ester moiety, and 22, with a C-28 ethyl hexanoate, increased the anti-HIV replication activity compared with 2 by 2-fold while compounds 40, 41, 48, and 49, with C-28 piperazine or piperidine amide substitutions, increased the activity by 3- to 15-fold. The best new compound, 41, exhibited an anti-HIV IC(50) of 0.0059 μM compared with 0.087 μM for 2. All of the active compounds showed only antimaturation effects, as confirmed by TZM-bl assay, in blocking the HIV replication. The results suggest that proper C-28 substitutions can further enhance the antimaturation activity of 2 without any antientry effects. Thus, 41 may serve as a promising new lead for development of anti-AIDS clinical trial candidates.
|
Antiviral activity against Human immunodeficiency virus 1 infected human H9 cells assessed as inhibition of viral replication
|
Human immunodeficiency virus 1
|
0.35
nM
|
|
Antiviral activity against Human immunodeficiency virus 1 infected human H9 cells assessed as inhibition of viral replication
|
Human immunodeficiency virus 1
|
0.2999
nM
|
|
Journal : Med Chem Res
Title : 3D-QSAR studies on betulinic acid and betulin derivatives as anti-HIV-1 agents using CoMFA and CoMSIA
Year : 2011
Volume : 20
Issue : 8
First Page : 1247
Last Page : 1259
Authors : Lan P, Chen W, Sun P, Chen W
|
Antiviral activity against 0.001 MOI wild type Human immunodeficiency virus 1 NL4-3 infected in human MT4 cells assessed as inhibition of viral replication measured 4 days post infection by ELISA
|
Human immunodeficiency virus 1
|
76.0
nM
|
|
Journal : J. Med. Chem.
Title : New betulinic acid derivatives for bevirimat-resistant human immunodeficiency virus type-1.
Year : 2013
Volume : 56
Issue : 5
First Page : 2029
Last Page : 2037
Authors : Dang Z, Ho P, Zhu L, Qian K, Lee KH, Huang L, Chen CH.
Abstract : Bevirimat (1, BVM) is an anti-HIV agent that blocks HIV-1 replication by interfering with HIV-1 Gag-SP1 processing at a late stage of viral maturation. However, clinical trials of 1 have revealed a high baseline drug resistance that is attributed to naturally occurring polymorphisms in HIV-1 Gag. To overcome the drug resistance, 28 new derivatives of 1 were synthesized and tested against compound 1-resistant (BVM-R) HIV-1 variants. Among them, compound 6 exhibited much improved activity against several HIV-1 strains carrying BVM-R polymorphisms. Compound 6 was at least 20-fold more potent than 1 against the replication of NL4-3/V370A, which carries the most prevalent clinical BVM-R polymorphism in HIV-1 Gag-SP1. Thus, compound 6 merits further development as a potential anti-AIDS clinical trial candidate.
|
Antiviral activity against HIV infected in H9 cells
|
Human immunodeficiency virus
|
0.35
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of a new derivative of bevirimat that targets the Gag CA-SP1 cleavage site.
Year : 2013
Volume : 62
First Page : 453
Last Page : 465
Authors : Coric P, Turcaud S, Souquet F, Briant L, Gay B, Royer J, Chazal N, Bouaziz S.
Abstract : Bevirimat (2), the first-in-class HIV-1 maturation inhibitor, shows a low efficacy due essentially to the natural polymorphism of its target, the CA-SP1 junction. Moreover, its low hydrosolubility makes it difficult to study its interaction with the CA-SP1 junction. We have synthesized new derivatives of bevirimat by adding different hydrophilic substituents at the C-28 position to improve their hydrosolubility and perform the structural study of a complex by NMR. Synthesis of the new derivatives, the effect of substituents at the C-28 position and their hydrosolubility are discussed. The ability of these molecules to inhibit viral infection and their cytotoxicity is assessed. Compared to the well-known bevirimat (2), one of our compounds (16) shows a higher hydrosolubility associated with a 2.5 fold increase in activity, a higher selectivity index and a better antiviral profile. Moreover, for the first time a direct interaction between a derivative of bevirimat (16) and the domain CA-SP1-NC is shown by NMR. Information from this study should allow us to decipher the mechanism by which bevirimat inhibits HIV-1 maturation and how the natural polymorphism of the spacer peptide SP1 triggers resistance to inhibitors.
|
Antiviral activity against HIV1 NL4.3 infected in MAGIC-5B cells after 48 hrs by beta-galactosidase reporter gene assay
|
Human immunodeficiency virus 1
|
40.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of a new derivative of bevirimat that targets the Gag CA-SP1 cleavage site.
Year : 2013
Volume : 62
First Page : 453
Last Page : 465
Authors : Coric P, Turcaud S, Souquet F, Briant L, Gay B, Royer J, Chazal N, Bouaziz S.
Abstract : Bevirimat (2), the first-in-class HIV-1 maturation inhibitor, shows a low efficacy due essentially to the natural polymorphism of its target, the CA-SP1 junction. Moreover, its low hydrosolubility makes it difficult to study its interaction with the CA-SP1 junction. We have synthesized new derivatives of bevirimat by adding different hydrophilic substituents at the C-28 position to improve their hydrosolubility and perform the structural study of a complex by NMR. Synthesis of the new derivatives, the effect of substituents at the C-28 position and their hydrosolubility are discussed. The ability of these molecules to inhibit viral infection and their cytotoxicity is assessed. Compared to the well-known bevirimat (2), one of our compounds (16) shows a higher hydrosolubility associated with a 2.5 fold increase in activity, a higher selectivity index and a better antiviral profile. Moreover, for the first time a direct interaction between a derivative of bevirimat (16) and the domain CA-SP1-NC is shown by NMR. Information from this study should allow us to decipher the mechanism by which bevirimat inhibits HIV-1 maturation and how the natural polymorphism of the spacer peptide SP1 triggers resistance to inhibitors.
|
Chemopreventive activity in human Raji cells assessed as molar ratio of compound required to inhibit 50% of control of inhibition of TPA-induced EBV-early antigen activation after 48 hrs by immunofluorescence analysis
|
Human herpesvirus 4
|
396.0
molar ratio
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A-ring modified betulinic acid derivatives as potent cancer preventive agents.
Year : 2014
Volume : 24
Issue : 3
First Page : 1005
Last Page : 1008
Authors : Hung HY, Nakagawa-Goto K, Tokuda H, Iida A, Suzuki N, Bori ID, Qian K, Lee KH.
Abstract : Ten new 3,4-seco betulinic acid (BA) derivatives were designed and synthesized. Among them, compounds 7-15 exhibited enhanced chemopreventive ability in an in vitro short-term 12-O-tetradecanoylphorbol-13-acetate (TPA) induced Epstein-Barr virus early antigen (EBV-EA) activation assay in Raji cells. Specifically, analogs with a free C-28 carboxylic acid, including 7, 8, 11, and 13, inhibited EBV-EA activation significantly. The most potent compound 8 displayed 100% inhibition at 1×10(3) mol ratio/TPA and 73.4%, 35.9%, and 8.4% inhibition at 5×10(2), 1×10(2), and 1×10 mol ratio/TPA, respectively, comparable with curcumin at high concentration and better than curcumin at low concentration. The potent chemopreventive activity of novel seco A-ring BAs (8 and 11) was further confirmed in an in vivo mouse skin carcinogenesis assay.
|
Antiviral activity against HIV1 NL4.3-Ren infected in human MT2 cells assessed as inhibition of viral growth at 10 uM measured 48 hrs post infection by luminometry
|
Human immunodeficiency virus 1
|
50.0
%
|
|
Journal : J. Nat. Prod.
Title : Isolation, Structural Modification, and HIV Inhibition of Pentacyclic Lupane-Type Triterpenoids from Cassine xylocarpa and Maytenus cuzcoina.
Year : 2015
Volume : 78
Issue : 5
First Page : 1045
Last Page : 1055
Authors : Callies O, Bedoya LM, Beltrán M, Muñoz A, Calderón PO, Osorio AA, Jiménez IA, Alcamí J, Bazzocchi IL.
Abstract : As a part of our investigation into new anti-HIV agents, we report herein the isolation, structure elucidation, and biological activity of six new (1-6) and 20 known (7-26) pentacyclic lupane-type triterpenoids from the stem of Cassine xylocarpa and root bark of Maytenus cuzcoina. Their stereostructures were elucidated on the basis of spectroscopic and spectrometric methods, including 1D and 2D NMR techniques. To gain a more complete understanding of the structural requirements for anti-HIV activity, derivatives 27-48 were prepared by chemical modification of the main secondary metabolites. Sixteen compounds from this series displayed inhibitory effects of human immunodeficiency virus type 1 replication with IC50 values in the micromolar range, highlighting compounds 12, 38, and 42 (IC50 4.08, 4.18, and 1.70 μM, respectively) as the most promising anti-HIV agents.
|
Antiviral activity against HIV1 NL4.3-Ren infected in human MT2 cells assessed as inhibition of viral growth measured 48 hrs post infection by luminometry
|
Human immunodeficiency virus 1
|
10.0
nM
|
|
Journal : J. Nat. Prod.
Title : Isolation, Structural Modification, and HIV Inhibition of Pentacyclic Lupane-Type Triterpenoids from Cassine xylocarpa and Maytenus cuzcoina.
Year : 2015
Volume : 78
Issue : 5
First Page : 1045
Last Page : 1055
Authors : Callies O, Bedoya LM, Beltrán M, Muñoz A, Calderón PO, Osorio AA, Jiménez IA, Alcamí J, Bazzocchi IL.
Abstract : As a part of our investigation into new anti-HIV agents, we report herein the isolation, structure elucidation, and biological activity of six new (1-6) and 20 known (7-26) pentacyclic lupane-type triterpenoids from the stem of Cassine xylocarpa and root bark of Maytenus cuzcoina. Their stereostructures were elucidated on the basis of spectroscopic and spectrometric methods, including 1D and 2D NMR techniques. To gain a more complete understanding of the structural requirements for anti-HIV activity, derivatives 27-48 were prepared by chemical modification of the main secondary metabolites. Sixteen compounds from this series displayed inhibitory effects of human immunodeficiency virus type 1 replication with IC50 values in the micromolar range, highlighting compounds 12, 38, and 42 (IC50 4.08, 4.18, and 1.70 μM, respectively) as the most promising anti-HIV agents.
|
Antiviral activity against HIV-1 NL4-3 infected in MT4 cells assessed inhibition of viral replication measured on day 4 postinfection by ELISA
|
Human immunodeficiency virus 1
|
75.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Fluorinated betulinic acid derivatives and evaluation of their anti-HIV activity.
Year : 2016
Volume : 26
Issue : 1
First Page : 68
Last Page : 71
Authors : Li J, Goto M, Yang X, Morris-Natschke SL, Huang L, Chen CH, Lee KH.
Abstract : Several fluorinated derivatives of the anti-HIV maturation agent bevirimat (1) were synthesized and evaluated for anti-HIV replication activity. The modified positions were the C-2, C-3, C-28, and C-30 positions, either directly on the betulinic acid (2) skeleton or in the attached side chains. Compound 18, which has a trifluoromethyl group added to C-30 of its isopropenyl group, exhibited similar potency to 1 against HIV-1NL4-3. In total, our current studies support our prior conclusion that C-30 allylic modification is unlikely to be a pharmacophore for anti-HIV activity, but could be a meaningful route to manipulate other properties of 2-related compounds.
|
Antiviral activity against wild type HIV1 NLRepRlucP373S infected in human MT2 cells after 4 to 5 days by luciferase report gene based multiple cycle drug susceptibility assay
|
Human immunodeficiency virus 1
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : C-3 benzoic acid derivatives of C-3 deoxybetulinic acid and deoxybetulin as HIV-1 maturation inhibitors.
Year : 2016
Volume : 24
Issue : 8
First Page : 1757
Last Page : 1770
Authors : Liu Z, Swidorski JJ, Nowicka-Sans B, Terry B, Protack T, Lin Z, Samanta H, Zhang S, Li Z, Parker DD, Rahematpura S, Jenkins S, Beno BR, Krystal M, Meanwell NA, Dicker IB, Regueiro-Ren A.
Abstract : A series of C-3 phenyl- and heterocycle-substituted derivatives of C-3 deoxybetulinic acid and C-3 deoxybetulin was designed and synthesized as HIV-1 maturation inhibitors (MIs) and evaluated for their antiviral activity and cytotoxicity in cell culture. A 4-subsituted benzoic acid moiety was identified as an advantageous replacement for the 3'3'-dimethylsuccinate moiety present in previously disclosed MIs that illuminates new aspects of the topography of the pharmacophore. The new analogs exhibit excellent in vitro antiviral activity against wild-type (wt) virus and a lower serum shift when compared with the prototypical HIV-1 MI bevirimat (1, BVM), the first MI to be evaluated in clinical studies. Compound 9a exhibits comparable cell culture potency toward wt virus as 1 (WT EC50=16 nM for 9a compared to 10nM for 1). However, the potency of 9a is less affected by the presence of human serum, while the compound displays a similar pharmacokinetic profile in rats to 1. Hence 9a, the 4-benzoic acid derivative of deoxybetulinic acid, represents a new starting point from which to explore the design of a 2nd generation MI.
|
Antiviral activity against wild type HIV1 NLRepRlucP373S infected in human MT2 cells after 4 to 5 days in presence of 15 mg/ml HSA by luciferase report gene based multiple cycle drug susceptibility assay
|
Human immunodeficiency virus 1
|
974.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : C-3 benzoic acid derivatives of C-3 deoxybetulinic acid and deoxybetulin as HIV-1 maturation inhibitors.
Year : 2016
Volume : 24
Issue : 8
First Page : 1757
Last Page : 1770
Authors : Liu Z, Swidorski JJ, Nowicka-Sans B, Terry B, Protack T, Lin Z, Samanta H, Zhang S, Li Z, Parker DD, Rahematpura S, Jenkins S, Beno BR, Krystal M, Meanwell NA, Dicker IB, Regueiro-Ren A.
Abstract : A series of C-3 phenyl- and heterocycle-substituted derivatives of C-3 deoxybetulinic acid and C-3 deoxybetulin was designed and synthesized as HIV-1 maturation inhibitors (MIs) and evaluated for their antiviral activity and cytotoxicity in cell culture. A 4-subsituted benzoic acid moiety was identified as an advantageous replacement for the 3'3'-dimethylsuccinate moiety present in previously disclosed MIs that illuminates new aspects of the topography of the pharmacophore. The new analogs exhibit excellent in vitro antiviral activity against wild-type (wt) virus and a lower serum shift when compared with the prototypical HIV-1 MI bevirimat (1, BVM), the first MI to be evaluated in clinical studies. Compound 9a exhibits comparable cell culture potency toward wt virus as 1 (WT EC50=16 nM for 9a compared to 10nM for 1). However, the potency of 9a is less affected by the presence of human serum, while the compound displays a similar pharmacokinetic profile in rats to 1. Hence 9a, the 4-benzoic acid derivative of deoxybetulinic acid, represents a new starting point from which to explore the design of a 2nd generation MI.
|
Antiviral activity against HIV1 containing gag V370A mutant infected in human MT2 cells after 4 to 5 days by luciferase report gene based multiple cycle drug susceptibility assay
|
Human immunodeficiency virus 1
|
553.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : C-3 benzoic acid derivatives of C-3 deoxybetulinic acid and deoxybetulin as HIV-1 maturation inhibitors.
Year : 2016
Volume : 24
Issue : 8
First Page : 1757
Last Page : 1770
Authors : Liu Z, Swidorski JJ, Nowicka-Sans B, Terry B, Protack T, Lin Z, Samanta H, Zhang S, Li Z, Parker DD, Rahematpura S, Jenkins S, Beno BR, Krystal M, Meanwell NA, Dicker IB, Regueiro-Ren A.
Abstract : A series of C-3 phenyl- and heterocycle-substituted derivatives of C-3 deoxybetulinic acid and C-3 deoxybetulin was designed and synthesized as HIV-1 maturation inhibitors (MIs) and evaluated for their antiviral activity and cytotoxicity in cell culture. A 4-subsituted benzoic acid moiety was identified as an advantageous replacement for the 3'3'-dimethylsuccinate moiety present in previously disclosed MIs that illuminates new aspects of the topography of the pharmacophore. The new analogs exhibit excellent in vitro antiviral activity against wild-type (wt) virus and a lower serum shift when compared with the prototypical HIV-1 MI bevirimat (1, BVM), the first MI to be evaluated in clinical studies. Compound 9a exhibits comparable cell culture potency toward wt virus as 1 (WT EC50=16 nM for 9a compared to 10nM for 1). However, the potency of 9a is less affected by the presence of human serum, while the compound displays a similar pharmacokinetic profile in rats to 1. Hence 9a, the 4-benzoic acid derivative of deoxybetulinic acid, represents a new starting point from which to explore the design of a 2nd generation MI.
|
Antiviral activity against HIV1 infected in human H9 cells
|
Human immunodeficiency virus 1
|
0.35
nM
|
|
Journal : Bioorg. Med. Chem.
Title : C-3 benzoic acid derivatives of C-3 deoxybetulinic acid and deoxybetulin as HIV-1 maturation inhibitors.
Year : 2016
Volume : 24
Issue : 8
First Page : 1757
Last Page : 1770
Authors : Liu Z, Swidorski JJ, Nowicka-Sans B, Terry B, Protack T, Lin Z, Samanta H, Zhang S, Li Z, Parker DD, Rahematpura S, Jenkins S, Beno BR, Krystal M, Meanwell NA, Dicker IB, Regueiro-Ren A.
Abstract : A series of C-3 phenyl- and heterocycle-substituted derivatives of C-3 deoxybetulinic acid and C-3 deoxybetulin was designed and synthesized as HIV-1 maturation inhibitors (MIs) and evaluated for their antiviral activity and cytotoxicity in cell culture. A 4-subsituted benzoic acid moiety was identified as an advantageous replacement for the 3'3'-dimethylsuccinate moiety present in previously disclosed MIs that illuminates new aspects of the topography of the pharmacophore. The new analogs exhibit excellent in vitro antiviral activity against wild-type (wt) virus and a lower serum shift when compared with the prototypical HIV-1 MI bevirimat (1, BVM), the first MI to be evaluated in clinical studies. Compound 9a exhibits comparable cell culture potency toward wt virus as 1 (WT EC50=16 nM for 9a compared to 10nM for 1). However, the potency of 9a is less affected by the presence of human serum, while the compound displays a similar pharmacokinetic profile in rats to 1. Hence 9a, the 4-benzoic acid derivative of deoxybetulinic acid, represents a new starting point from which to explore the design of a 2nd generation MI.
|
Antiviral activity against wild type HIV1 NL4-3 infected in human MT2 cells after 4 to 5 days by dual-luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibitors of HIV-1 maturation: Development of structure-activity relationship for C-28 amides based on C-3 benzoic acid-modified triterpenoids.
Year : 2016
Volume : 26
Issue : 8
First Page : 1925
Last Page : 1930
Authors : Swidorski JJ, Liu Z, Sit SY, Chen J, Chen Y, Sin N, Venables BL, Parker DD, Nowicka-Sans B, Terry BJ, Protack T, Rahematpura S, Hanumegowda U, Jenkins S, Krystal M, Dicker IB, Meanwell NA, Regueiro-Ren A.
Abstract : We have recently reported on the discovery of a C-3 benzoic acid (1) as a suitable replacement for the dimethyl succinate side chain of bevirimat (2), an HIV-1 maturation inhibitor that reached Phase II clinical trials before being discontinued. Recent SAR studies aimed at improving the antiviral properties of 2 have shown that the benzoic acid moiety conferred topographical constraint to the pharmacophore and was associated with a lower shift in potency in the presence of human serum albumin. In this manuscript, we describe efforts to improve the polymorphic coverage of the C-3 benzoic acid chemotype through modifications at the C-28 position of the triterpenoid core. The dimethylaminoethyl amides 17 and 23 delivered improved potency toward bevirimat-resistant viruses while increasing C24 in rat oral PK studies.
|
Antiviral activity against wild type HIV1 NL4-3 infected in human MT2 cells after 4 to 5 days by dual-luciferase reporter gene assay in presence of human serum albumin
|
Human immunodeficiency virus 1
|
974.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibitors of HIV-1 maturation: Development of structure-activity relationship for C-28 amides based on C-3 benzoic acid-modified triterpenoids.
Year : 2016
Volume : 26
Issue : 8
First Page : 1925
Last Page : 1930
Authors : Swidorski JJ, Liu Z, Sit SY, Chen J, Chen Y, Sin N, Venables BL, Parker DD, Nowicka-Sans B, Terry BJ, Protack T, Rahematpura S, Hanumegowda U, Jenkins S, Krystal M, Dicker IB, Meanwell NA, Regueiro-Ren A.
Abstract : We have recently reported on the discovery of a C-3 benzoic acid (1) as a suitable replacement for the dimethyl succinate side chain of bevirimat (2), an HIV-1 maturation inhibitor that reached Phase II clinical trials before being discontinued. Recent SAR studies aimed at improving the antiviral properties of 2 have shown that the benzoic acid moiety conferred topographical constraint to the pharmacophore and was associated with a lower shift in potency in the presence of human serum albumin. In this manuscript, we describe efforts to improve the polymorphic coverage of the C-3 benzoic acid chemotype through modifications at the C-28 position of the triterpenoid core. The dimethylaminoethyl amides 17 and 23 delivered improved potency toward bevirimat-resistant viruses while increasing C24 in rat oral PK studies.
|
Antiviral activity against wild type HIV1 NL4-3 habouring Gag protein V370A mutant infected in human MT2 cells after 4 to 5 days by dual-luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
553.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibitors of HIV-1 maturation: Development of structure-activity relationship for C-28 amides based on C-3 benzoic acid-modified triterpenoids.
Year : 2016
Volume : 26
Issue : 8
First Page : 1925
Last Page : 1930
Authors : Swidorski JJ, Liu Z, Sit SY, Chen J, Chen Y, Sin N, Venables BL, Parker DD, Nowicka-Sans B, Terry BJ, Protack T, Rahematpura S, Hanumegowda U, Jenkins S, Krystal M, Dicker IB, Meanwell NA, Regueiro-Ren A.
Abstract : We have recently reported on the discovery of a C-3 benzoic acid (1) as a suitable replacement for the dimethyl succinate side chain of bevirimat (2), an HIV-1 maturation inhibitor that reached Phase II clinical trials before being discontinued. Recent SAR studies aimed at improving the antiviral properties of 2 have shown that the benzoic acid moiety conferred topographical constraint to the pharmacophore and was associated with a lower shift in potency in the presence of human serum albumin. In this manuscript, we describe efforts to improve the polymorphic coverage of the C-3 benzoic acid chemotype through modifications at the C-28 position of the triterpenoid core. The dimethylaminoethyl amides 17 and 23 delivered improved potency toward bevirimat-resistant viruses while increasing C24 in rat oral PK studies.
|
Antiviral activity against wild type BVM-resistant HIV1 NL4-3 habouring Gag protein T371A mutant infected in human MT2 cells after 4 to 5 days by dual-luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
40.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibitors of HIV-1 maturation: Development of structure-activity relationship for C-28 amides based on C-3 benzoic acid-modified triterpenoids.
Year : 2016
Volume : 26
Issue : 8
First Page : 1925
Last Page : 1930
Authors : Swidorski JJ, Liu Z, Sit SY, Chen J, Chen Y, Sin N, Venables BL, Parker DD, Nowicka-Sans B, Terry BJ, Protack T, Rahematpura S, Hanumegowda U, Jenkins S, Krystal M, Dicker IB, Meanwell NA, Regueiro-Ren A.
Abstract : We have recently reported on the discovery of a C-3 benzoic acid (1) as a suitable replacement for the dimethyl succinate side chain of bevirimat (2), an HIV-1 maturation inhibitor that reached Phase II clinical trials before being discontinued. Recent SAR studies aimed at improving the antiviral properties of 2 have shown that the benzoic acid moiety conferred topographical constraint to the pharmacophore and was associated with a lower shift in potency in the presence of human serum albumin. In this manuscript, we describe efforts to improve the polymorphic coverage of the C-3 benzoic acid chemotype through modifications at the C-28 position of the triterpenoid core. The dimethylaminoethyl amides 17 and 23 delivered improved potency toward bevirimat-resistant viruses while increasing C24 in rat oral PK studies.
|
Antiviral activity against wild type BVM-resistant HIV1 NL4-3 habouring Gag protein delta T371 infected in human MT2 cells after 4 to 5 days by dual-luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
77.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibitors of HIV-1 maturation: Development of structure-activity relationship for C-28 amides based on C-3 benzoic acid-modified triterpenoids.
Year : 2016
Volume : 26
Issue : 8
First Page : 1925
Last Page : 1930
Authors : Swidorski JJ, Liu Z, Sit SY, Chen J, Chen Y, Sin N, Venables BL, Parker DD, Nowicka-Sans B, Terry BJ, Protack T, Rahematpura S, Hanumegowda U, Jenkins S, Krystal M, Dicker IB, Meanwell NA, Regueiro-Ren A.
Abstract : We have recently reported on the discovery of a C-3 benzoic acid (1) as a suitable replacement for the dimethyl succinate side chain of bevirimat (2), an HIV-1 maturation inhibitor that reached Phase II clinical trials before being discontinued. Recent SAR studies aimed at improving the antiviral properties of 2 have shown that the benzoic acid moiety conferred topographical constraint to the pharmacophore and was associated with a lower shift in potency in the presence of human serum albumin. In this manuscript, we describe efforts to improve the polymorphic coverage of the C-3 benzoic acid chemotype through modifications at the C-28 position of the triterpenoid core. The dimethylaminoethyl amides 17 and 23 delivered improved potency toward bevirimat-resistant viruses while increasing C24 in rat oral PK studies.
|
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
|
10.0
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 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
|
552.0
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
|
74.0
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 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
|
7.0
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 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
|
40.0
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
|
77.0
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.
|
Antiviral activity against wild type HIV1 NL4-3 infected in human MT4 cells by p24 ELISA
|
Human immunodeficiency virus 1
|
65.0
nM
|
|
Journal : J Med Chem
Title : Incorporation of Privileged Structures into Bevirimat Can Improve Activity against Wild-Type and Bevirimat-Resistant HIV-1.
Year : 2016
Volume : 59
Issue : 19
First Page : 9262
Last Page : 9268
Authors : Zhao Y, Gu Q, Morris-Natschke SL, Chen CH, Lee KH.
Abstract : Two "privileged fragments", caffeic acid and piperazine, were integrated into bevirimat producing new derivatives with improved activity against HIV-1/NL4-3 and NL4-3/V370A carrying the most prevalent bevirimat-resistant polymorphism. The activity of one of these, 18c, was increased by 3-fold against NL4-3 and 51-fold against NL4-3/V370A. Moreover, 18c is a maturation inhibitor with improved metabolic stability. Our study suggested that integration of privileged motifs into promising natural product skeletons is an effective strategy for discovering potent derivatives.
|
Inhibition of wild type HIV-1 clade B NL4-3 Gag polyprotein SP1 infected in human MT4 cells
|
Human immunodeficiency virus 1
|
270.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of a novel and potent class of anti-HIV-1 maturation inhibitors with improved virology profile against gag polymorphisms.
Year : 2017
Volume : 27
Issue : 12
First Page : 2689
Last Page : 2694
Authors : Tang J, Jones SA, Jeffrey JL, Miranda SR, Galardi CM, Irlbeck DM, Brown KW, McDanal CB, Johns BA.
Abstract : A new class of betulin-derived α-keto amides was identified as HIV-1 maturation inhibitors. Through lead optimization, GSK8999 was identified with IC50 values of 17nM, 23nM, 25nM, and 8nM for wild type, Q369H, V370A, and T371A respectively. When tested in a panel of 62 HIV-1 isolates covering a diversity of CA-SP1 genotypes including A, AE, B, C, and G using a PBMC based assay, GSK8999 was potent against 57 of 62 isolates demonstrating an improvement over the first generation maturation inhibitor BVM. The data disclosed here also demonstrated that the new α-keto amide GSK8999 has a mechanism of action consistent with inhibition of the proteolytic cleavage of CA-SP1.
|
Inhibition of bevirimat-resistant HIV1 clade B NL4-3 CA-SP1 Q369H mutant infected in human MT4 cells
|
Human immunodeficiency virus 1
|
383.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of a novel and potent class of anti-HIV-1 maturation inhibitors with improved virology profile against gag polymorphisms.
Year : 2017
Volume : 27
Issue : 12
First Page : 2689
Last Page : 2694
Authors : Tang J, Jones SA, Jeffrey JL, Miranda SR, Galardi CM, Irlbeck DM, Brown KW, McDanal CB, Johns BA.
Abstract : A new class of betulin-derived α-keto amides was identified as HIV-1 maturation inhibitors. Through lead optimization, GSK8999 was identified with IC50 values of 17nM, 23nM, 25nM, and 8nM for wild type, Q369H, V370A, and T371A respectively. When tested in a panel of 62 HIV-1 isolates covering a diversity of CA-SP1 genotypes including A, AE, B, C, and G using a PBMC based assay, GSK8999 was potent against 57 of 62 isolates demonstrating an improvement over the first generation maturation inhibitor BVM. The data disclosed here also demonstrated that the new α-keto amide GSK8999 has a mechanism of action consistent with inhibition of the proteolytic cleavage of CA-SP1.
|
Inhibition of bevirimat-resistant HIV1 clade B NL4-3 CA-SP1 T371A mutant infected in human MT4 cells
|
Human immunodeficiency virus 1
|
252.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of a novel and potent class of anti-HIV-1 maturation inhibitors with improved virology profile against gag polymorphisms.
Year : 2017
Volume : 27
Issue : 12
First Page : 2689
Last Page : 2694
Authors : Tang J, Jones SA, Jeffrey JL, Miranda SR, Galardi CM, Irlbeck DM, Brown KW, McDanal CB, Johns BA.
Abstract : A new class of betulin-derived α-keto amides was identified as HIV-1 maturation inhibitors. Through lead optimization, GSK8999 was identified with IC50 values of 17nM, 23nM, 25nM, and 8nM for wild type, Q369H, V370A, and T371A respectively. When tested in a panel of 62 HIV-1 isolates covering a diversity of CA-SP1 genotypes including A, AE, B, C, and G using a PBMC based assay, GSK8999 was potent against 57 of 62 isolates demonstrating an improvement over the first generation maturation inhibitor BVM. The data disclosed here also demonstrated that the new α-keto amide GSK8999 has a mechanism of action consistent with inhibition of the proteolytic cleavage of CA-SP1.
|
Antiviral activity against Human immunodeficiency virus assessed as reduction in maturation
|
Human immunodeficiency virus
|
10.3
nM
|
|
Journal : J Med Chem
Title : Natural-Products-Inspired Use of the gem-Dimethyl Group in Medicinal Chemistry.
Year : 2018
Volume : 61
Issue : 6
First Page : 2166
Last Page : 2210
Authors : Talele TT.
Abstract : The gem-dimethyl moiety is a structural feature frequently found in many natural products of clinical interest, including, but not limited to, taxanes, epothilones, statins, retinoids, di-/triterpenes, noviose deoxysugar, and antibiotics derived from β-lactams, macrolides, and aminocoumarins. Inspired by this time-tested moiety, medicinal chemists have widely explored its use in developing bioactive molecules because of the possibility to (1) increase target engagement, potency, and selectivity through van der Waals interactions and entropically favorable restriction to a bioactive conformation, (2) mitigate toxicity, (3) obtain superior DMPK profile, (4) modulate the p Ka of nearby functionality, (5) induce symmetry into a monomethyl substituted chiral center, and (6) apply the Thorpe-Ingold conformational effect in an o-hydroxydihydrocinnamic acid based prodrug design. The aim of this Perspective is to illustrate how medicinal chemists have elegantly employed the gem-dimethyl group to obtain clinically useful drugs and to provide synthetic methods to install a gem-dimethyl group.
|
Binding affinity to CA-SP1 P373S mutant in HIV-1 subtype B NL4-3 infected in human MT2 cells assessed as inhibition of viral maturation by measuring virus yields after 4 to 5 days in presence of 10% FBS by luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
10.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : The design, synthesis and structure-activity relationships associated with C28 amine-based betulinic acid derivatives as inhibitors of HIV-1 maturation.
Year : 2018
Volume : 28
Issue : 9
First Page : 1550
Last Page : 1557
Authors : Chen Y, Sit SY, Chen J, Swidorski JJ, Liu Z, Sin N, Venables BL, Parker DD, Nowicka-Sans B, Lin Z, Li Z, Terry BJ, Protack T, Rahematpura S, Hanumegowda U, Jenkins S, Krystal M, Dicker ID, Meanwell NA, Regueiro-Ren A.
Abstract : The design and synthesis of a series of C28 amine-based betulinic acid derivatives as HIV-1 maturation inhibitors is described. This series represents a continuation of efforts following on from previous studies of C-3 benzoic acid-substituted betulinic acid derivatives as HIV-1 maturation inhibitors (MIs) that were explored in the context of C-28 amide substituents. Compared to the C-28 amide series, the C-28 amine derivatives exhibited further improvements in HIV-1 inhibitory activity toward polymorphisms in the Gag polyprotein as well as improved activity in the presence of human serum. However, plasma exposure of basic amines following oral administration to rats was generally low, leading to a focus on moderating the basicity of the amine moiety distal from the triterpene core. The thiomorpholine dioxide (TMD) 20 emerged from this study as a compound with the optimal antiviral activity and an acceptable pharmacokinetic profile in the C-28 amine series. Compared to the C-28 amide 3, 20 offers a 2- to 4-fold improvement in potency towards the screening viruses, exhibits low shifts in the EC50 values toward the V370A and ΔV370 viruses in the presence of human serum or human serum albumin, and demonstrates improved potency towards the polymorphic T371A and V362I virus variants.
|
Binding affinity to CA-SP1 P373S mutant in HIV-1 subtype B NL4-3 infected in human MT2 cells assessed as inhibition of viral maturation by measuring virus yields after 4 to 5 days in presence of 10% FBS/15 mg/ml HSA by luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
970.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : The design, synthesis and structure-activity relationships associated with C28 amine-based betulinic acid derivatives as inhibitors of HIV-1 maturation.
Year : 2018
Volume : 28
Issue : 9
First Page : 1550
Last Page : 1557
Authors : Chen Y, Sit SY, Chen J, Swidorski JJ, Liu Z, Sin N, Venables BL, Parker DD, Nowicka-Sans B, Lin Z, Li Z, Terry BJ, Protack T, Rahematpura S, Hanumegowda U, Jenkins S, Krystal M, Dicker ID, Meanwell NA, Regueiro-Ren A.
Abstract : The design and synthesis of a series of C28 amine-based betulinic acid derivatives as HIV-1 maturation inhibitors is described. This series represents a continuation of efforts following on from previous studies of C-3 benzoic acid-substituted betulinic acid derivatives as HIV-1 maturation inhibitors (MIs) that were explored in the context of C-28 amide substituents. Compared to the C-28 amide series, the C-28 amine derivatives exhibited further improvements in HIV-1 inhibitory activity toward polymorphisms in the Gag polyprotein as well as improved activity in the presence of human serum. However, plasma exposure of basic amines following oral administration to rats was generally low, leading to a focus on moderating the basicity of the amine moiety distal from the triterpene core. The thiomorpholine dioxide (TMD) 20 emerged from this study as a compound with the optimal antiviral activity and an acceptable pharmacokinetic profile in the C-28 amine series. Compared to the C-28 amide 3, 20 offers a 2- to 4-fold improvement in potency towards the screening viruses, exhibits low shifts in the EC50 values toward the V370A and ΔV370 viruses in the presence of human serum or human serum albumin, and demonstrates improved potency towards the polymorphic T371A and V362I virus variants.
|
Binding affinity to CA-SP1 P373S/V370A double mutant in HIV-1 subtype B NL4-3 infected in human MT2 cells assessed as inhibition of viral maturation by measuring virus yield after 4 to 5 days in presence of 10% FBS by luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
552.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : The design, synthesis and structure-activity relationships associated with C28 amine-based betulinic acid derivatives as inhibitors of HIV-1 maturation.
Year : 2018
Volume : 28
Issue : 9
First Page : 1550
Last Page : 1557
Authors : Chen Y, Sit SY, Chen J, Swidorski JJ, Liu Z, Sin N, Venables BL, Parker DD, Nowicka-Sans B, Lin Z, Li Z, Terry BJ, Protack T, Rahematpura S, Hanumegowda U, Jenkins S, Krystal M, Dicker ID, Meanwell NA, Regueiro-Ren A.
Abstract : The design and synthesis of a series of C28 amine-based betulinic acid derivatives as HIV-1 maturation inhibitors is described. This series represents a continuation of efforts following on from previous studies of C-3 benzoic acid-substituted betulinic acid derivatives as HIV-1 maturation inhibitors (MIs) that were explored in the context of C-28 amide substituents. Compared to the C-28 amide series, the C-28 amine derivatives exhibited further improvements in HIV-1 inhibitory activity toward polymorphisms in the Gag polyprotein as well as improved activity in the presence of human serum. However, plasma exposure of basic amines following oral administration to rats was generally low, leading to a focus on moderating the basicity of the amine moiety distal from the triterpene core. The thiomorpholine dioxide (TMD) 20 emerged from this study as a compound with the optimal antiviral activity and an acceptable pharmacokinetic profile in the C-28 amine series. Compared to the C-28 amide 3, 20 offers a 2- to 4-fold improvement in potency towards the screening viruses, exhibits low shifts in the EC50 values toward the V370A and ΔV370 viruses in the presence of human serum or human serum albumin, and demonstrates improved potency towards the polymorphic T371A and V362I virus variants.
|
Binding affinity to CA-SP1 P373S/T371A double mutant in HIV-1 subtype B NL4-3 infected in human MT2 cells assessed as inhibition of viral maturation by measuring virus yield after 4 to 5 days in presence of 10% FBS by luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
10.4
nM
|
|
Journal : Bioorg Med Chem Lett
Title : The design, synthesis and structure-activity relationships associated with C28 amine-based betulinic acid derivatives as inhibitors of HIV-1 maturation.
Year : 2018
Volume : 28
Issue : 9
First Page : 1550
Last Page : 1557
Authors : Chen Y, Sit SY, Chen J, Swidorski JJ, Liu Z, Sin N, Venables BL, Parker DD, Nowicka-Sans B, Lin Z, Li Z, Terry BJ, Protack T, Rahematpura S, Hanumegowda U, Jenkins S, Krystal M, Dicker ID, Meanwell NA, Regueiro-Ren A.
Abstract : The design and synthesis of a series of C28 amine-based betulinic acid derivatives as HIV-1 maturation inhibitors is described. This series represents a continuation of efforts following on from previous studies of C-3 benzoic acid-substituted betulinic acid derivatives as HIV-1 maturation inhibitors (MIs) that were explored in the context of C-28 amide substituents. Compared to the C-28 amide series, the C-28 amine derivatives exhibited further improvements in HIV-1 inhibitory activity toward polymorphisms in the Gag polyprotein as well as improved activity in the presence of human serum. However, plasma exposure of basic amines following oral administration to rats was generally low, leading to a focus on moderating the basicity of the amine moiety distal from the triterpene core. The thiomorpholine dioxide (TMD) 20 emerged from this study as a compound with the optimal antiviral activity and an acceptable pharmacokinetic profile in the C-28 amine series. Compared to the C-28 amide 3, 20 offers a 2- to 4-fold improvement in potency towards the screening viruses, exhibits low shifts in the EC50 values toward the V370A and ΔV370 viruses in the presence of human serum or human serum albumin, and demonstrates improved potency towards the polymorphic T371A and V362I virus variants.
|
Binding affinity to CA-SP1 P373S/V362I double mutant in HIV-1 subtype B NL4-3 infected in human MT2 cells assessed as inhibition of viral maturation by measuring virus yield after 4 to 5 days in presence of 10% FBS by luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
74.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : The design, synthesis and structure-activity relationships associated with C28 amine-based betulinic acid derivatives as inhibitors of HIV-1 maturation.
Year : 2018
Volume : 28
Issue : 9
First Page : 1550
Last Page : 1557
Authors : Chen Y, Sit SY, Chen J, Swidorski JJ, Liu Z, Sin N, Venables BL, Parker DD, Nowicka-Sans B, Lin Z, Li Z, Terry BJ, Protack T, Rahematpura S, Hanumegowda U, Jenkins S, Krystal M, Dicker ID, Meanwell NA, Regueiro-Ren A.
Abstract : The design and synthesis of a series of C28 amine-based betulinic acid derivatives as HIV-1 maturation inhibitors is described. This series represents a continuation of efforts following on from previous studies of C-3 benzoic acid-substituted betulinic acid derivatives as HIV-1 maturation inhibitors (MIs) that were explored in the context of C-28 amide substituents. Compared to the C-28 amide series, the C-28 amine derivatives exhibited further improvements in HIV-1 inhibitory activity toward polymorphisms in the Gag polyprotein as well as improved activity in the presence of human serum. However, plasma exposure of basic amines following oral administration to rats was generally low, leading to a focus on moderating the basicity of the amine moiety distal from the triterpene core. The thiomorpholine dioxide (TMD) 20 emerged from this study as a compound with the optimal antiviral activity and an acceptable pharmacokinetic profile in the C-28 amine series. Compared to the C-28 amide 3, 20 offers a 2- to 4-fold improvement in potency towards the screening viruses, exhibits low shifts in the EC50 values toward the V370A and ΔV370 viruses in the presence of human serum or human serum albumin, and demonstrates improved potency towards the polymorphic T371A and V362I virus variants.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
15.36
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Antiviral activity against HIV1 NL4-3 infected in human MT4 cells by luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
26.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery and synthesis of novel beesioside I derivatives with potent anti-HIV activity.
Year : 2019
Volume : 166
First Page : 159
Last Page : 166
Authors : Wu H, Ma G, Yang Q, Zhu Y, Huang L, Tian Y, Yang X, Zhang M, Chen CH, Morris-Natschke SL, Yang M, Xu X, Lee KH.
Abstract : In this study, 12 known cycloartane triterpenoids (1-12) with four different skeletons isolated from the roots of Souliea vaginata were screened for the first time for in vitro anti-HIV activity using AZT as a standard. Among the compounds, beesioside I (1) showed the highest potency against HIV-1NL4-3 with an EC50 value of 2.32 μM (CC50 > 40 μM). Preliminary structure-activity relationship (SAR) studies on 1 indicated that simple modification of its aglycone (13) could significantly influence the antiviral activity. Particularly, the introduction of an acyl group at the C-3 position of 13 led to significant improvement in both anti-HIV potency and selectivity index. Among all synthetically modified derivatives, compound 13g was the most potent compound with an EC50 value of 0.025 μM and TI value greater than 800, comparable to those of 3-O-(3',3'-dimethylsuccinyl)-betulinic acid (DSB, bevirimat). Other analogues exhibited strong to weak inhibition of HIV-1 replication in MT-4 cells. The length, carboxylic terminus, and C-3' dimethyl substitution of the C-3 side chain substantially affected the anti-HIV activity. Finally, compound 13g was an effective agent against HIV with high potential for further investigation.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
10.87
%
|
|
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
|
0.13
%
|
|
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
|
0.13
%
|
|
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.
|
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
|
9.0
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
|
553.0
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
|
974.0
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
|
74.0
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
|
8.0
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
|
111.0
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
|
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 deltaThr371 mutant assessed as inhibition of HIV-1 maturation
|
Human immunodeficiency virus 1
|
77.0
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 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
|
10.0
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 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
|
552.0
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 HIV 1 NL4-3 infected in human MT4 cells assessed as reduction in viral replication and measured on day 3 post infection by Nano-glo luciferase reporter assay
|
Homo sapiens
|
21.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Novel Betulinic Acid-Nucleoside Hybrids with Potent Anti-HIV Activity.
Year : 2020
Volume : 11
Issue : 11
First Page : 2290
Last Page : 2293
Authors : Wang Q,Li Y,Zheng L,Huang X,Wang Y,Chen CH,Cheng YY,Morris-Natschke SL,Lee KH
Abstract : Novel betulinic/betulonic acid-nucleoside hybrids were synthesized as possible new anti-HIV agents. Among the synthesized hybrids, two compounds were highly effective against HIV. Compared with AZT and DSB, compounds 10a (IC = 0.0078 μM, CC = 9.6 μM) and 10b (IC = 0.020 μM, CC = 23.8 μM) showed more potent or equipotent, respectively, anti-HIV activity but displayed lower cytotoxicity.
|
Antiviral activity against HIV-1 NL4-3 infected in human MT4 cells assessed as reduction in p24 gag protein incubated for 4 days by ELISA
|
Human immunodeficiency virus 1
|
64.57
nM
|
|
Antiviral activity against HIV-1 NL4-3 infected in human MT4 cells assessed as reduction in p24 gag protein incubated for 4 days by ELISA
|
Human immunodeficiency virus 1
|
65.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and structure activity relationship analysis of new betulinic acid derivatives as potent HIV inhibitors.
Year : 2021
Volume : 215
First Page : 113287
Last Page : 113287
Authors : Zhao Y,Chen CH,Morris-Natschke SL,Lee KH
Abstract : Prior modification of betulinic acid (1), a natural product lead with promising anti-HIV activity, produced 3-O-(3',3'-dimethylsuccinyl)betulinic acid (bevirimat, 3), the first-in-class HIV maturation inhibitor. After 3-resistant variants were found during Phase I and IIa clinical trials, further modification of 3 produced 4 with improved activity against wild-type and 3-resistant HIV-1. In continued efforts to optimize 1, 63 final products have now been designed, synthesized, and evaluated for anti-HIV-1 replication activity against HIV-1 infected MT-4 cell lines. Five known and 21 new derivatives were as or more potent than 3 (EC 0.065 μM), while eight new derivatives were as or more potent than 4 (EC 0.019 μM). These derivatives feature expanded structural diversity and chemical space that may improve the antiviral activity and address the growing resistance crisis. Structure-Activity Relationship (SAR) correlations were thoroughly analyzed, and a 3D Quantitative SAR model with high predictability was constructed to facilitate further rational design and development of new potent derivatives.
