203576-71-0Relevant articles and documents
Anti-AIDS agents - XXVII. Synthesis and anti-HIV activity of betulinic acid and dihydrobetulinic acid derivatives
Hashimoto, Fumio,Kashiwada, Yoshiki,Cosentino, L. Mark,Chen, Chin-Ho,Garrett, Patricia E.,Lee, Kuo-Hsiung
, p. 2133 - 2143 (1997)
Two series of lupane-type triterpenoic acid derivatives were synthesized and evaluated for their inhibitory activity against HIV-1 replication in acutely infected H9 cells, based on the fact that betulinic acid (1) and dihydrobetulinic acid (9) were identified as anti-HIV agents. Among the derivatives, 3-O-(3',3'-dimethylsuccinyl)-betulinic acid (3) and 3-O-(3',3'-dimethylsuccinyl)-dihydrobetulinic acid (11) both demonstrated extremely potent inhibitory activity with EC50 values of -4 μM, and remarkable in vitro therapeutic index (TI) values of 20,000 and 14,000, respectively. 3-O-(3',3'-dimethylglutaryl)-betulinic acid (4) and -dihydrobetulinic acid (12), 3-O-diglycolyl-betulinic acid (5) and -dihydrobetulinic acid (13) and 3-O-glutaryl-betulinic acid (6) were also potent inhibitors of HIV replication with EC50 values ranging from 0.04 to 2.3 x 10-3 μM and TI values from 292 to 2344. In addition, compounds 11 and 12 were also active against HIV replication in a monocyte cell line and in peripheral blood mononuclear cells. Our in vitro assay indicated that these compounds are not inhibitors of HIV-1 reverse transcriptase, whereas they inhibited syncytia formation completely in a concentration range of 20-40 μg/mL. However, 3-O-(2',2'-dimethylsuccinyl)-betulinic acid (2) was also found to be an inhibitor of HIV-induced membrane fusion with an IC100 value of 20 μg/mL, though it displayed significantly lower anti-HIV activity than foregoing compounds with an EC50 value of 2.7 μM and TI of 6.7. Further study is underway to determine the mechanisms of action of these compounds.
Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176)
Regueiro-Ren, Alicia,Swidorski, Jacob J.,Liu, Zheng,Chen, Yan,Sin, Ny,Sit, Sing-Yuen,Chen, Jie,Venables, Brian L.,Zhu, Juliang,Nowicka-Sans, Beata,Protack, Tricia,Lin, Zeyu,Terry, Brian,Samanta, Himadri,Zhang, Sharon,Li, Zhufang,Easter, John,Beno, Brett R.,Arora, Vinod,Huang, Xiaohua S.,Rahematpura, Sandhya,Parker, Dawn D.,Haskell, Roy,Santone, Kenneth S.,Cockett, Mark I.,Krystal, Mark,Meanwell, Nicholas A.,Jenkins, Susan,Hanumegowda, Umesh,Dicker, Ira B.
, p. 7289 - 7313 (2018/09/06)
GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC50 15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.
NOVEL C28-ANALOGUES WITH C3-MODIFICATIONS OF TRITERPENE DERIVATIVES AS HIV INHIBITORS
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Page/Page column 57, (2017/03/08)
The present invention relates to compounds of novel C28-analogues with C3- modifications of triterpene derivatives of formula (I); or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, tautomers, stereoisomers, prodrugs, compositions or combination thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, X, and Z are as defined herein. The present invention also relates to pharmaceutical compositions comprising compounds of formula (I) useful for the treatment of viral diseases and particularly HIV mediated diseases.
Discovery of BMS-955176, a Second Generation HIV-1 Maturation Inhibitor with Broad Spectrum Antiviral Activity
Regueiro-Ren, Alicia,Liu, Zheng,Chen, Yan,Sin, Ny,Sit, Sing-Yuen,Swidorski, Jacob J.,Chen, Jie,Venables, Brian L.,Zhu, Juliang,Nowicka-Sans, Beata,Protack, Tricia,Lin, Zeyu,Terry, Brian,Samanta, Himadri,Zhang, Sharon,Li, Zhufang,Beno, Brett R.,Huang, Xiaohua S.,Rahematpura, Sandhya,Parker, Dawn D.,Haskell, Roy,Jenkins, Susan,Santone, Kenneth S.,Cockett, Mark I.,Krystal, Mark,Meanwell, Nicholas A.,Hanumegowda, Umesh,Dicker, Ira B.
supporting information, p. 568 - 572 (2016/07/06)
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.
