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A novel, picomolar inhibitor of human immunodeficiency virus type 1 protease. 1996
H L Sham, and
C Zhao, and
K D Stewart, and
D A Betebenner, and
S Lin, and
C H Park, and
X P Kong, and
W Rosenbrook, and
T Herrin, and
D Madigan, and
S Vasavanonda, and
N Lyons, and
A Molla, and
A Saldivar, and
K C Marsh, and
E McDonald, and
N E Wideburg, and
J F Denissen, and
T Robins, and
D J Kempf, and
J J Plattner, and
D W Norbeck
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500.
The design, synthesis, and molecular modeling studies of a novel series of azacyclic ureas, which are inhibitors of human immunodeficiency virus type 1 (HIV-1) protease that incorporate different ligands for the S1', S2, and S2' substrate-binding sites of HIV-1 protease are described. The synthesis of this series is highly flexible in the sense that the P1', P2, and P2' residues of the inhibitors can be changed independently. Molecular modeling studies on the phenyl ring of the P2 and P2' ligand suggested incorporation of hydrogen-bonding donor/acceptor groups at the 3' and 4-positions of the phenyl ring should increase binding potency. This led to the discovery of compound 7f (A-98881), which possesses high potency in the HIV-1 protease inhibition assay and the in vitro MT-4 cell culture assay (Ki = approximately 5 pM and EC50 = 0.002 microM). This compares well with the symmetrical cyclic urea 1 pioneered at DuPont Merck.
Related Publications
H L Sham, and
C Zhao, and
K D Stewart, and
D A Betebenner, and
S Lin, and
C H Park, and
X P Kong, and
W Rosenbrook, and
T Herrin, and
D Madigan, and
S Vasavanonda, and
N Lyons, and
A Molla, and
A Saldivar, and
K C Marsh, and
E McDonald, and
N E Wideburg, and
J F Denissen, and
T Robins, and
D J Kempf, and
J J Plattner, and
D W Norbeck
April 2008,
Antimicrobial agents and chemotherapy,
H L Sham, and
C Zhao, and
K D Stewart, and
D A Betebenner, and
S Lin, and
C H Park, and
X P Kong, and
W Rosenbrook, and
T Herrin, and
D Madigan, and
S Vasavanonda, and
N Lyons, and
A Molla, and
A Saldivar, and
K C Marsh, and
E McDonald, and
N E Wideburg, and
J F Denissen, and
T Robins, and
D J Kempf, and
J J Plattner, and
D W Norbeck
May 2000,
Clinical therapeutics,
H L Sham, and
C Zhao, and
K D Stewart, and
D A Betebenner, and
S Lin, and
C H Park, and
X P Kong, and
W Rosenbrook, and
T Herrin, and
D Madigan, and
S Vasavanonda, and
N Lyons, and
A Molla, and
A Saldivar, and
K C Marsh, and
E McDonald, and
N E Wideburg, and
J F Denissen, and
T Robins, and
D J Kempf, and
J J Plattner, and
D W Norbeck
April 2002,
Antiviral research,
H L Sham, and
C Zhao, and
K D Stewart, and
D A Betebenner, and
S Lin, and
C H Park, and
X P Kong, and
W Rosenbrook, and
T Herrin, and
D Madigan, and
S Vasavanonda, and
N Lyons, and
A Molla, and
A Saldivar, and
K C Marsh, and
E McDonald, and
N E Wideburg, and
J F Denissen, and
T Robins, and
D J Kempf, and
J J Plattner, and
D W Norbeck
October 2000,
Archives of biochemistry and biophysics,
H L Sham, and
C Zhao, and
K D Stewart, and
D A Betebenner, and
S Lin, and
C H Park, and
X P Kong, and
W Rosenbrook, and
T Herrin, and
D Madigan, and
S Vasavanonda, and
N Lyons, and
A Molla, and
A Saldivar, and
K C Marsh, and
E McDonald, and
N E Wideburg, and
J F Denissen, and
T Robins, and
D J Kempf, and
J J Plattner, and
D W Norbeck
September 2000,
Virology,
H L Sham, and
C Zhao, and
K D Stewart, and
D A Betebenner, and
S Lin, and
C H Park, and
X P Kong, and
W Rosenbrook, and
T Herrin, and
D Madigan, and
S Vasavanonda, and
N Lyons, and
A Molla, and
A Saldivar, and
K C Marsh, and
E McDonald, and
N E Wideburg, and
J F Denissen, and
T Robins, and
D J Kempf, and
J J Plattner, and
D W Norbeck
June 2005,
Antimicrobial agents and chemotherapy,
H L Sham, and
C Zhao, and
K D Stewart, and
D A Betebenner, and
S Lin, and
C H Park, and
X P Kong, and
W Rosenbrook, and
T Herrin, and
D Madigan, and
S Vasavanonda, and
N Lyons, and
A Molla, and
A Saldivar, and
K C Marsh, and
E McDonald, and
N E Wideburg, and
J F Denissen, and
T Robins, and
D J Kempf, and
J J Plattner, and
D W Norbeck
May 1997,
Archives of internal medicine,
H L Sham, and
C Zhao, and
K D Stewart, and
D A Betebenner, and
S Lin, and
C H Park, and
X P Kong, and
W Rosenbrook, and
T Herrin, and
D Madigan, and
S Vasavanonda, and
N Lyons, and
A Molla, and
A Saldivar, and
K C Marsh, and
E McDonald, and
N E Wideburg, and
J F Denissen, and
T Robins, and
D J Kempf, and
J J Plattner, and
D W Norbeck
April 1994,
Proceedings of the National Academy of Sciences of the United States of America,
H L Sham, and
C Zhao, and
K D Stewart, and
D A Betebenner, and
S Lin, and
C H Park, and
X P Kong, and
W Rosenbrook, and
T Herrin, and
D Madigan, and
S Vasavanonda, and
N Lyons, and
A Molla, and
A Saldivar, and
K C Marsh, and
E McDonald, and
N E Wideburg, and
J F Denissen, and
T Robins, and
D J Kempf, and
J J Plattner, and
D W Norbeck
March 2002,
The Pediatric infectious disease journal,
H L Sham, and
C Zhao, and
K D Stewart, and
D A Betebenner, and
S Lin, and
C H Park, and
X P Kong, and
W Rosenbrook, and
T Herrin, and
D Madigan, and
S Vasavanonda, and
N Lyons, and
A Molla, and
A Saldivar, and
K C Marsh, and
E McDonald, and
N E Wideburg, and
J F Denissen, and
T Robins, and
D J Kempf, and
J J Plattner, and
D W Norbeck
January 1995,
Journal of cellular biochemistry. Supplement,
