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

Article abstract of DOI:10.1021/acsmedchemlett.6b00010

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.

Full text of DOI:10.1021/acsmedchemlett.6b00010

Letter
pubs.acs.org/acsmedchemlett
Discovery of BMS-955176, a Second Generation HIV‑1 Maturation
Inhibitor with Broad Spectrum Antiviral Activity
Alicia Regueiro-Ren,*,† Zheng Liu,† Yan Chen,† Ny Sin,† Sing-Yuen Sit,† Jacob J. Swidorski,† Jie Chen,†
Brian L. Venables,† Juliang Zhu,‡ Beata Nowicka-Sans,§,# Tricia Protack,§ Zeyu Lin,§ Brian Terry,§
Himadri Samanta,§ Sharon Zhang,§ Zhufang Li,§ Brett R. Beno,∥ Xiaohua S. Huang,⊥
Sandhya Rahematpura,⊥ Dawn D. Parker,⊥ Roy Haskell,⊥ Susan Jenkins,⊥ Kenneth S. Santone,⊥
Mark I. Cockett,§ Mark Krystal,§ Nicholas A. Meanwell,† Umesh Hanumegowda,⊥ and Ira B. Dicker§
‡
§
∥
⊥
†Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical
Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492,
United States
S
* Supporting Information
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.
KEYWORDS: HIV-1, maturation inhibitors, BMS-955176, betulinic acid, triterpene, antiviral
IV-1 infection can be effectively managed with current
derived from betulinic acid (BA, 10).5,6 At the highest doses
Htreatments that rely on long-term administration of (150 and 250 mg), a maximal viral load reduction (VLR) of
0.72 log10 was observed. However, in the Phase IIa trial with
highly experienced patients, only 45% of individuals responded
to treatment with an HIV-1 RNA change from baseline of >0.5
log10, and only 34% with >1 log10 VLR.7 The restricted
response to 1 was subsequently determined to be a
consequence of naturally occurring polymorphic variation at
Gag amino acid residues 369−371.8−10 The lack of
polymorphic coverage in combination with difficulties in
formulation ultimately led to a halt in the development of
1.11,12 Three other modified triterpenoid MIs have been
evaluated in humans, but none of these compounds have
advanced beyond Phase I clinical studies.13−15
In order to drive the discovery of a second generation MI
with broad polymorphic coverage, it was important to maintain
activity against the key polymorphic variation at V370.16
Therefore, we chose the V370A- and ΔV370-containing viruses
as the primary screening viruses due to their high prevalence in
B and non-B subtypes, respectively, and their high level
resistance to BVM.17 Additional improvements in a second
multiple antiviral inhibitors designated as combination
antiretroviral therapy (cART).1 Nevertheless, the development
of novel agents with improved safety profiles and different
mechanisms of action (MOA) is still highly desirable due to
long-term toxicity and resistance development with current
therapies. New ARTs would preferentially exhibit minimal
drug−drug interactions with a relatively low once-daily dose to
facilitate combinations with other agents as part of a fixed dose
regimen.2
In the latter stages of the virus life cycle, the HIV-1 matrix
(MA), capsid (CA), nucleocapsid (NC), and p6 proteins are
released from the Gag polyprotein via multiple cleavages made
by the viral protease. The final and rate-limiting step in this
maturation process is cleavage at the CA-SP1 junction, which
induces a major structural change within the virion, leading to
the formation of the conical core that is characteristic of an
infectious virion. Maturation inhibitors (MIs) prevent repli-
cation by binding near the CA-SP1 segment of the Gag
polyprotein, specifically blocking only this final rate-limiting
cleavage event, leading to the production of immature,
noninfectious particles.3,4
Received: January 9, 2016
Accepted: April 20, 2016
Proof-of-concept for this MOA was demonstrated in a 10 day
Phase I/II monotherapy trial with bevirimat,(1, Chart 1), an MI
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.6b00010
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
Chart 1. Selected HIV-1 Maturation Inhibitors
Table 1. HIV-1 Inhibition and Rat AUC0‑6h of Compounds 1−9
a
WT EC50 (nM)
b
c
WT
WT + HS
V370A
ΔV370
>10,000
CC50 (μM)
Rat AUC0−6h (nM*h)
1
2
3
4
5
6
7
8
9
10 11
1.9 1.8
16 13
2.3 1.3
2.2 0.7
2.2
1,291 1,011
552 633
2.7 1.5
233 305
7.8 8.8
2.5 2.2
12
16.8 14.5
6,390
d
10.2
6
13 11
>6,000
9.2
4
4,132 685
5,724
105 40
27.2 38.5
2.61 1.78
1.24 0.16
2.36
d
43 29
31 19
20.6 14
61
1, 623 240
8.7
153
-
-
0.7 0.2
1.0 0.4
1.9 1.2
-
1.7 0.7
2.5 1.4
9.9 2.8
9.9 8.3
14.566 8.4
66 53
5.8 0.8
3.5 1.6
8.48 5.34
1,044
1,708
5.7 3.1
-
4,983
a
b
The antiviral activity of the compounds was assessed in a multiple cycle assay in MT-2 cells in 10% fetal bovine serum (FBS). Compounds
evaluated for serum effects in 10% FBS + 40% human serum except for 2 (10% FBS + 40% human serum + 27 mg/mL human serum albumin);
c
d
values are means from experiments performed a minimum of three times (n ≥ 3). Dose 5 mg/kg po, n = 2; see SI for vehicle information. n = 3.
generation MI would be lower binding to human serum
components that decreased the effective potency of 1 (human
serum (HS) binding >99%)17 and an improvement in physical
properties that would allow for an appropriate formulation that
could deliver targeted concentrations in vivo. Herein, we
describe the discovery of BMS-955176 (2), an orally efficacious,
second generation HIV-1 maturation inhibitor that is currently
in Phase IIb clinical trials.18 The complete virology profile of
BMS-955176 (2) is described in a companion manuscript, and
resistance studies have been completed and will be published
elsewhere.17
The description of the effect of Gag polymorphisms on the
antiviral response to bevirimat (1) stimulated our interest in
maturation inhibition as a target, since this identified a
screening paradigm, but there was no evidence in the literature
that structural modification of 1 could address the fundamental
problem. As the first step in our study of this chemotype, we
explored changes to the succinic acid-based side chain at C-3, a
moiety that appeared to have largely been accepted as a
pharmacophoric element, with a view to revealing key aspects
of the topography of the carboxylic acid while providing new
opportunities for structural modification.19,20 The benzoic acid
derivative 3 emerged very quickly from that effort, exhibiting
good antiviral activity against wild-type (WT) virus, a modest 7-
fold shift in the presence of HS, and good oral exposure in rats
(Table 1). The para-substitution pattern in 3 was critical for
antiviral activity. However, potency against Gag V370A, the
most prevalent polymorphism in the region of Gag associated
with MI activity, was lacking.19
Attention was then directed toward derivatization of the C-
28 position of 3, where an extensive series of analogues were
prepared that incorporated a wide range of functionality.
Amides such as 4, incorporating a basic side chain, provided
excellent potency against both WT and V370A viruses, while
maintaining a low human serum shift (∼4-fold). In addition, 4
exhibited an EC50 of 31 nM against the ΔV370 Gag
polymorphism. However, 4 exhibited low oral exposure,
attributed to a combination of poor solubility and low
membrane permeability, precluding its further advancement.20
With further probing of this region, the dibasic C-28 amine 5
was found to retain good polymorphic coverage, but displayed
even lower oral exposure than 4, while the more lipophilic
monobasic isopropyl amine 6 exhibited 3- to 5-fold reduced
activity toward the polymorphic viruses, demonstrating that a
single amine installed close to the core was acceptable.21
Based on this discovery, the introduction of a nonbasic polar
group in the side chain was probed with 7, which improved the
antiviral profile of 6, with EC50 values of <10 nM against the 3
screening viruses (Table 1).22 However, while this combination
of basicity and polarity afforded good polymorphic coverage,
B
DOI: 10.1021/acsmedchemlett.6b00010
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
Table 2. Antiviral Activity of Bevirimat (1) and BMS-955176 (2) toward HIV-1 Viruses Containing Naturally-Occurring
a
,
Polymorphisms in the Gag Protein17
EC50
V362I
Q369H
V370M
V370A/ΔT371
ΔV371A
ΔT371
bevirimat (1)
74 59
7.0 2.0
1.9 0.9
1,810 190
2.8 0.3
1,114 119
3.6 3.9
40 48
77 97
BMS-955176 (2)
4.5 2.2
2.0 0.1
7.3 3.9
a
Values are means from experiments performed a minimum of three times (n ≥ 3).
poor oral exposure in rats (AUC0−6h of 7 in rats =1,044 nM·h)
remained an issue. The introduction of a moderately basic
amine, 1,1-dioxidothiomorpholine heterocycle, pKa = 4.5,23
provided 8, which demonstrated targeted antiviral activity and
improved oral exposure in rats, although still 2- to 3-fold less
than for 1 and 3. We hypothesized that installing the more
basic amine closer to the lipophilic core would have the effect
of shielding the NH and may have a positive impact on the
permeability properties of the molecule and, ultimately, on oral
exposure. This concept was initially probed with the alcohol 9,
which exhibited improved oral exposure (AUC0−6h in rats =
4,983 nM·h), although at the expense of reduced activity
toward the polymorphic viruses, particularly ΔV370.24 With
further experimentation, merging the C-17 amine with the 1,1-
dioxidothiomorpholine heterocycle of 8 provided BMS-955176
(2), a compound with an optimal combination of antiviral
potency and oral exposure. This compound exhibits excellent
potency toward the key Gag mutations, with EC50 values of 1.9,
2.7, and 13 nM against WT, V370A, and ΔV370 viruses,
respectively. Furthermore, following oral dosing of 5 mg/kg of
BMS-955176 to rats, the AUC0−6h was 4,132 nM·h,
demonstrating exposure comparable to 1 (Table 1). In the
presence of HS, BMS-955176 exhibited a ∼5-fold reduction in
antiviral activity, reflecting moderate serum binding (deter-
mined to be 84% using an ultracentrifugation method).17 The
potent antiviral activity of 2 extended to a library of clinically
relevant isolates (N = 87), representing sequence variability in
the 362−370 Gag region of subtype B viruses, with a mean
EC50 value of 3.9 3.4 nM.17 In addition, other site directed
Gag polymorphisms known to be resistant to 1 were
introduced into a laboratory strain, with the results for a select
group compiled in Table 2, illustrating that 2 retains activity
toward all of these viruses.17 BMS-955176 was shown to be an
MI by a series of mechanistic experiments which ruled out
entry, reverse transcription, and protease as targets, while
demonstrating that 2 acts late in the viral life cycle. The
compound binds saturably and reversibly to HIV-1 Gag
pseudoparticles and this binding is specifically displaced by 1.
In addition, 2 specifically inhibits cleavage of CA/SP1 p25,
resulting in inhibition of the production of capsid p24.17
The metabolic stability of 2 in vitro was high, with a t1/2 of
>120 min when incubated in human, rat, and dog liver
microsomes in the presence of NADPH, predicting low
clearance in vivo. However, in monkey liver microsomes, 2
exhibited high metabolic turnover, with a t1/2 of only 12 min. It
was not possible to accurately assess the in vitro permeability of
2 due to limited solubility under the assay conditions, but it is
presumed to be satisfactory, since 2 demonstrated good oral
exposure in rats, with an AUCtotal of 14,198 nM·h after a dose
of 5 mg/kg (Table 3). In this experiment, the C24 of 2 was 128
nM, 21-fold higher than that of 1 under comparable
circumstances. The oral bioavailability (%F) of 2 ranged from
low in the dog and cynomologus monkey, reflecting the
reduced metabolic stability in the latter species, to moderate in
Table 3. In Vivo Pharmacokinetic Properties of BMS-
955176 in Mice, Rats, Dogs, and Cynomolgus Monkeys
a
b
c
d
F (%)
AUCtotal (nM·h)
C24 (nM)
IV t1/2 (h)
Mouse
Rat
27
28,912
256 78
128 27
559 345
17.4 10.9
8.9
26
14,198 1,083
29,358 16,436
995 318
6.6
Dog
8.5
3.9
31.7
8.6
Cyno
a
Oral vehicle (solution): 90% polyethylene glycol 300 (PEG 300),
b
10% EtOH, n = 3; dose = 5 mg/kg PO. Oral vehicle (solution):
84.5% PEG 300, 10% EtOH, 50.1 N NaOH and 0.5% Tween 80
c
(TW80), n = 3; dose = 5 mg/kg PO. Oral vehicle (solution): 80% 50
mM citrate buffer; 20% sulfobutylether-beta-cyclodextrin (SBC), pH =
d
3, n = 3; dose = 1.85 mg/kg. Oral vehicle (solution): 80% 50 mM
citrate buffer; 20% SBC, pH = 3, n = 3; dose = 2 mg/kg.
mice and rats, with long t1/2 values in all species tested.
Allometric scaling and mean residence time methodology using
data from all four species were used to predict the human PK
profile of 2, which, combined with a targeted Ctrough value of
281 nM (3-fold the protein binding-adjusted EC90 vs the
ΔV370 virus), indicated that 2 may be suitable for once-daily
administration of reasonable low doses (≤120 mg). Efficacy at
these doses has been confirmed in clinical studies.25 Safety
profiling of BMS-955176 showed no evidence of mutagenicity
in an Ames reverse mutation assay, and low potential for off-
target liabilities based on evaluation in a panel of receptor, ion
channel, and enzyme activity assays. There was also a low
potential for drug−drug interactions based on CYP450 human
microsomal inhibition assays.
The synthesis of 2 (BMS-955176) is shown in Scheme 1.22
Commercially available 10 was treated with benzyl bromide in
the presence of K2CO3, followed by oxidation with PCC to
afford ketone 11, which was converted into the enol triflate 12.
Suzuki coupling of 12 with (4-(methoxycarbonyl)phenyl)-
boronic acid afforded 13. The C-28 carboxylic acid in 13 was
selectively deprotected using tert-butyldimethylsilane in the
presence of Pd(OAc)2 to afford silyl ester 14, which upon
treatment with TBAF generated 15. Curtius rearrangement of
15 using DPPA afforded the C-17 primary amine 17 in a
process that could be carried out either in a single operation or
stepwise via isolation of the corresponding C-28 isocyanate 16.
Derivatization of the primary amine in 17 turned out to be a
challenge, presumably due to a combination of steric hindrance
and decreased nucleophilicity of the N atom caused by its
proximity to the steroid core. A 3-step procedure was initially
developed to install the side chain present in 2 via reductive
amination of 17 using tert-butyl 2-oxoethylcarbamate in the
presence of NaBH(OAc)3 and Ti(OiPr)4, which rendered 18.
The BOC protecting group was removed using HCl to provide
the C-17 primary amine 19. In situ trapping of 19 via a double
Michael addition to divinylsulfone afforded 20, with an overall
yield of 38% for the 3-step procedure. Ultimately, the reductive
amination/hydrolysis/Michael addition sequence was replaced
C
DOI: 10.1021/acsmedchemlett.6b00010
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
a
Scheme 1. Synthesis of 2 (BMS-955176)
a
Reagents and conditions: (a) K2CO3, BnBr, DMF, 60 °C, 3.5 h, 99%; (b) PCC, CH2Cl2, 6 h, 96%; (c) KHMDS, PhNTf2, THF, −78 °C, 4 h, 90%;
(d) (4-(methoxycarbonyl)phenyl)boronic acid, Na2CO3, Pd(Ph3P)4, 1,4-dioxane/i-PrOH/H2O, reflux, 14.5 h, 68.1%; (e) TBDMSH, Pd(OAc)2,
TEA, DCE, 60 °C, 2 h, 97%; (f) TBAF, H2O/1,4-dioxane, rt, 4 h, 99%; (g) DPPA, TEA, 1,4-dioxane, 100 °C, 5 h, 93%; (h) conc. HCl, THF, rt, 72
h, quant.; (i) Na(OAc)3BH, Ti(OiPr)4, DCE, rt, 19 h 79%; (j) HCl, 1,4-dioxane, rt, 4 h, 95%; (k) TEA, 1,4-dioxane/EtOH, 85 °C, 3 h, 91%; (l)
K3PO4, KI, MeCN, 115−125 °C, 48 h, 73%; (m) NaOH, 1,4-dioxane, 78 °C, 3 h, 77%.
by a one-step procedure in which 17 was alkylated with 4-(2-
chloroethyl)thiomorpholine 1,1-dioxide to afford 20 in 73%
yield. This combination of base and solvent appeared to be
optimal in order to achieve the complete conversion of 17 to
20. Final hydrolysis of 20 to unmask the carboxylic acid was
performed with aqueous NaOH to afford 2 (BMS-955176).
Overall, 2 was prepared in 10 steps from 10 with a total yield of
20%.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.6b00010.
Characterization data for key compounds and exper-
imental procedures for the preparation of 2, as well as
descriptions of biologic and pharmacokinetic assays
(PDF)
In conclusion, BMS-955176 is a potent HIV-1 inhibitor in
cell culture that, unlike 1, exhibits broad spectrum antiviral
effects that encompass the V370A- and ΔV370-containing
polymorphic viruses. In addition, BMS-955176 exhibits low
serum binding, which translates into a modest 5-fold effect on
potency in vitro, and preclinical PK predictive of once-daily
dosing in humans. In a Phase IIa clinical trial, 10-days of
monotherapy with 2 administered daily to treatment-naive and
treatment-experienced subjects infected with HIV-1 subtypes B
or C was generally safe and well-tolerated and demonstrated >1
log10 reduction in viral RNA.18,25 BMS-955176 is currently
being evaluated in a Phase IIb clinical study as a part of a
treatment regimen with mechanistically different antiretroviral
agents.
AUTHOR INFORMATION
■
Corresponding Author
*Tel, +1 203 677 7416; fax, +1 203 677 7884; E-mail, Alicia.
regueiroren@bms.com.
Notes
#Deceased April eighth, 2016.
The authors declare the following competing financial interest:
The authors were employees of Bristol-Myers Squibb at the
time this work was completed.
ACKNOWLEDGMENTS
■
The authors would like to acknowledge the experimental
support of the Bioanalytical group.
D
DOI: 10.1021/acsmedchemlett.6b00010
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
(14) Baichwal, V.; Austin, H.; Brown, B.; McKinnon, R.; Yager, K.;
Kumar, V.; Gerrish, D.; Anderson, M.; Carlson, R. Anti-viral
characterization in vitro of a novel maturation inhibitor, MPC-9055.
16th Conference on Retroviruses and Opportunistic Infections, Montreal,
Canada. February 8−11, 2009. Abstract #J-105.
(15) U.S. National Institutes of Health. A repeat dose pharmacoki-
netic (PK) and safety study of GSK2838232 with and without ritonavir
(RTV) conducted in healthy subjects. https://www.clinicaltrials.gov/
ct2/show/NCT02289495?term=GSK2838232&rank=1.
(16) Dang, Z.; Ho, P.; Zhu, L.; Qian, K.; Lee, K.-H.; Huang, L.;
Chen, C.-H. New betulinic acid derivatives for bevirimat-resistant
human immunodeficiency virus type-1. J. Med. Chem. 2013, 56, 2029−
2037.
(17) Nowicka-Sans, B.; Protack, T.; Lin, Z.; Li, Z.; Zhang, S.;
Samanta, H.; Terry, B.; Liu, Z.; Chen, Y.; Sin, N.; Sit, S.-Y.; Swidorski,
J. J.; Chen, J.; Venables, B. L.; Healy, M.; Sun, Y.; Meanwell, N. A.;
Cockett, M.; Hanumegowda, U.; Regueiro-Ren, A.; Krystal, M.;
Dicker, I. B. BMS-955176: identification and characterization of a
second-generation HIV 1 maturation inhibitor with improved potency,
anti-viral spectrum and Gag polymorphic coverage. Antimicrob. Agents
Chemother. 2016, DOI: 10.1128/AAC.02560-15.
DEDICATION
■
This article is dedicated to the memory of Beata Nowicka-Sans,
who passed away on April 8th, 2016.
ABBREVIATIONS
■
AUC, area under the curve; BA, betulinic acid; CA, capsid;
cART, combination antiretroviral therapy; Cyno, cynomolo-
gous monkey; DCE, dichloroethane; DCM, methylene
chloride; DME, 1,2-dimethoxyethane; DMF, dimethylforma-
mide; F, oral bioavailability; FBS, fetal bovine serum; HS,
human serum; KHMDS, potassium bis(trimethylsilyl)amide;
LANL, Los Alamos National Laboratory; MA, matrix; MI,
maturation inhibitor; MeOH, methanol; MOA, mechanism of
action; NC, nucleocapsid; NFV, nelfinavir; PCC, pyridinium
chlorochromate; PEG, polyethylene glycol; PK, pharmacoki-
netic; PO, per os; rt, room temperature; SP, spacer peptide;
TBDMSH, tert-butyldimethylsilylhydride; TEA, trimethyl-
amine; TFA, trifluoroacetic acid; THF, tetrahydrofuran; TW,
tween; VLR, viral load reduction; WT, wild-type
(18) Hwang, C.; Schurmann, D.; Shobotha, C.; Sevinsky, H.;
̈
Ravindran, P.; Xiao, H.; Ray, N.; Krystal, M.; Dicker, I. B.; Lataillade,
M. Antiviral activity/safety of a second generation HIV-1 maturation
inhibitor. 22nd Conference on Retroviruses and Opportunistic Infections,
Seattle, WA, February 23−26, 2015. Abstract #114LB.
(19) Liu, Z.; Swidorski, J. J.; Nowicka-Sans, B.; Terry, B.; Protack, T.;
Lin, Z.; Samanta, H.; Zhang, S.; Li, Z.; Rahematpura, S.; Parker, D. D.;
Jenkins, S.; Beno, B. R.; Krystal, M.; Meanwell, N. A.; Dicker, I. B.;
Regueiro-Ren, A. C-3 benzoic acid derivatives of C-3 deoxybetulinic
acid and deoxybetuline as HIV-1 maturation inhibitors. Bioorg. Med.
Chem. 2016, 24, 1757−1770.
(20) Swidorski, J. J.; Liu, Z.; Sit, S.-Y.; Chen, J.; Chen, Y.; Sin, N.;
Venables, B. L.; Nowicka-Sans, B.; Protack, T.; Lin, Z.; Terry, B.;
Zhang, S.; Li, Z.; Rahematpura, S.; Parker, D. D.; Jenkins, S.; Krystal,
M.; Hanumegowda, U.; Dicker, I. B.; Meanwell, N. A.; Regueiro-Ren,
A. Inhibitors of HIV-1 maturation: development of structure-activity
relationships for C-28 amide derivatives of C-3 benzoic acid-modified
triterpenoids. Bioorg. Med. Chem. Lett. 2016, 26, 1925−1930.
(21) Urano, E.; Alban, S. D.; Mandt, R.; Pauly, G. T.; Sigano, D. M.;
Schneider, J. P.; Martin, D. E.; Nitz, T. J.; Wild, C. T.; Freed, E. O.
Antimicrob. Agents Chemother. 2016, 60, 190−197.
REFERENCES
■
(1) Taiwo, B.; Hicks, C.; Eron, J. Unmet therapeutic needs in the
new era of combination antiretroviral therapy for HIV-1. J. Antimicrob.
Chemother. 2010, 65, 1100−1107.
(2) Pau, A. K.; George, J. M. Antiretroviral therapy. Infect. Dis. Clin. N.
Am. 2014, 28, 371−402.
(3) Sundquist, W. I.; Krausslich, H. G. HIV-1 assembly, budding, and
̈
maturation. Cold Spring Harbor Perspect. Med. 2012, 7, a006924.
(4) Freed, E. O. HIV-1 assembly, release and maturation. Nat. Rev.
Microbiol. 2015, 13, 484−496.
(5) Martin, D. E.; Salzwedel, K.; Allaway, G. P. Bevirimat: a novel
maturation inhibitor for the treatment of HIV-1 infection. Antiviral
Chem. Chemother. 2008, 19, 107−113.
(6) Temesgen, Z.; Feinberg, J. E. Drug evaluation: bevirimat - HIV
Gag protein and viral maturation inhibitor. Curr. Opin. Investig. Drugs
2006, 7, 759−765.
(7) Smith, P. F.; Ogundele, A.; Forrest, J. W.; Salzweded, K.; Doto, J.;
Allaway, G. P.; Martin, D. E. 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. Antimicrob. Agents Chemo-
ther. 2007, 51, 3574−3581.
(22) Regueiro-Ren, A.; Swidorski, J.; Sit, S.; Chen, Y.; Chen, J.;
Meanwell, N. A.; Liu, Z.; C-28 amines of C-3 modified betulinic acid
derivatives as HIV maturation inhibitors. U.S. Patent 8,748,415, June
10, 2014.
(8) McCallister, S.; Lalezari, J.; Richmond, G.; Thompson, M.;
Harrigan, R.; Martin, D.; Salzwedel, K.; Allaway, G. HIV-1 Gag
polymorphisms determine treatment response to bevirimat (PA-457).
Antiviral Ther. 2008, 13, A10.
(9) Van Baelen, K. V.; Salzwedel, K.; Rondelez, E.; Veerle Van Eygen,
V. V.; De Vos, S.; Verheyen, A.; Steegen, K.; Verlinden, Y.; Allaway, G.
P.; Stuyver, L. J. Susceptibility of human immunodeficiency virus type
1 to the maturation inhibitor bevirimat is modulated by baseline
polymorphisms in Gag spacer peptide 1. Antimicrob. Agents Chemother.
2009, 53, 2185−2188.
(10) Margot, N. A.; Gibbs, C. S.; Miller, M. D. Phenotypic
susceptibility to bevirimat among HIV-1 infected patient isolates
without prior exposure to bevirimat. Antimicrob. Agents Chemother.
2010, 54, 2345−2353.
(23) Martin, R. E.; Plancq, B.; Gavelle, O.; Wagner, B.; Fischer, H.;
Bendels, S.; Muller, K. ChemMedChem 2007, 2, 285−287.
̈
(24) C-17 and C-3 modified triterpenoids with HIV maturation
inhibitory activity. Regueiro-Ren, A.; Liu, Z.; Swidorski, J.; Sin, N.;
Venables, B. L.; Sit, S.; Chen, Y.; Chen, J.; Meanwell, N. A.; Modified
C-3 betulinic acid derivatives as HIV maturation inhibitors. U.S. Patent
8,846,647, September 30, 2014.
(25) Hwang, C.; Schartman, R.; Sobotha, C.; Boffito, M.; Sevinsky,
H.; Ray, N.; Ravindran, P.; Xiao, H.; Krystal, M.; Dicker, I.; Grasela,
D.; Lataillade, M. Overall antiviral activity and safety results from the
Phase IIa proof-of-concept study (AI468002). 15th European AIDS
Conference; October 21−24, 2015. Barcelona, Spain.
(11) Jacob, J.; Richards, J.; Augustine, J. G.; Milea, J. S. Liquid
bevirimat dosage forms for oral administration. World Patent
Application, WO 2009/042166 A1. November 5, 2009.
(12) Wainberg, M. A.; Albert, J. Can the further clinical development
of bevirimat be justified? AIDS 2010, 24, 773−774.
(13) Kilgore, N.; Reddick, M.; Zuiderhof, M.; Stanley, D.; Nitz, T.;
Bullock, P.; Allaway, G.; Martin, D. Characterization of PA1050040, a
second generation HIV-1 maturation inhibitor. Poster discussion: 4th
IAS Conference on HIV Pathogenesis, Treatment and Prevention. Sydney,
Australia July 22−25, 2007. Abstract no. MOPDX05.
E
DOI: 10.1021/acsmedchemlett.6b00010
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX