Discovery of BMS-955176, a Second Generation HIV-1 Maturation Inhibitor with Broad Spectrum Antiviral Activity.
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.
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Alicia
A
Regueiro-Ren
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Zheng
Z
Liu
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Yan
Y
Chen
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Ny
N
Sin
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Sing-Yuen
SY
Sit
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Jacob J
JJ
Swidorski
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Jie
J
Chen
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Brian L
BL
Venables
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Juliang
J
Zhu
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Beata
B
Nowicka-Sans
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Tricia
T
Protack
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Zeyu
Z
Lin
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Brian
B
Terry
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Himadri
H
Samanta
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Sharon
S
Zhang
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Zhufang
Z
Li
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Brett R
BR
Beno
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Xiaohua S
XS
Huang
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Sandhya
S
Rahematpura
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Dawn D
DD
Parker
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Roy
R
Haskell
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Susan
S
Jenkins
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Kenneth S
KS
Santone
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Mark I
MI
Cockett
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Mark
M
Krystal
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Nicholas A
NA
Meanwell
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Umesh
U
Hanumegowda
Departments of Discovery Chemistry, Chemical Synthesis, Virology, Computer-Assisted Drug Design, and Pharmaceutical Candidate Optimization, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Ira B
IB
Dicker
BMS-955176; HIV-1; antiviral; betulinic acid; maturation inhibitors; triterpene