Design, synthesis, and biological evaluation of monopyrrolinone-based HIV-1 protease inhibitors

Journal of Medicinal Chemistry

Volumn 46, Issue 10, 2003, Pages 1831-1844

  Smith III, Amos B ^a   Cantin, Louis David ^a   Pasternak, Alexander ^a   Guise Zawacki, Lisa ^a   Yao, Wenquin ^a   Charnley, Adam K ^a   Barbosa, Joseph ^a   Sprengeler, Paul A ^a   Hirschmann, Ralph ^a   Munshi, Sanjeev ^b   Olsen, David B ^b   Schleif, William A ^b   Kuo, Lawrence C ^b  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

^b MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ASPARTIC ACID; BUTYLOXYCARBONYLPYRROLINONE INHIBITOR; CARBAMIC ACID; INDINAVIR; MUTANT PROTEIN; PROTEINASE; PROTEINASE INHIBITOR; PYRROLINE DERIVATIVE; TETRAHYDROFURANYLCARBAMATE PYRROLINONE; TETRAHYDROISOQUINOLYL INHIBITOR; UNCLASSIFIED DRUG; WATER;

ANIMAL EXPERIMENT; ANTIVIRAL ACTIVITY; ARTICLE; BINDING AFFINITY; CELL TRANSPORT; CHEMICAL REACTION; CONTROLLED STUDY; CRYSTALLIZATION; DISTRIBUTION VOLUME; DOG; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG DESIGN; DRUG EFFICACY; DRUG HALF LIFE; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG UPTAKE; ENZYME BINDING; ENZYME INHIBITION; HUMAN IMMUNODEFICIENCY VIRUS 1; HYDROGEN BOND; MOLECULAR INTERACTION; MOLECULAR WEIGHT; NONHUMAN; STRUCTURE ANALYSIS; X RAY ANALYSIS;

ANIMALS; BIOLOGICAL AVAILABILITY; CARBAMATES; CRYSTALLOGRAPHY, X-RAY; DOGS; DRUG DESIGN; HIV PROTEASE; HIV PROTEASE INHIBITORS; MODELS, MOLECULAR; MUTATION; PROTEIN BINDING; PYRROLES;

EID: 0037740657     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0204587     Document Type: Article

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71. Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J.; Miyashiro, J. M.; Rowell, B. W.; Yu, S. S. Improved procedure for the reduction of N-acyloxazolidinones. Synth. Commun. 1990, 20, 307-312. For preparation, see Tararov, V. I.; Kuznetznov, N. Y.; Bakhmutov, V. I.; Ikonnikov, T. F.; Bubnov, Y. N.; Khrustalev, V. N.; Saveleva, T. F.; Belokon, Y. N. Remarkable Dependence of the Regioselectivity of Free Radical Additions to 3-Cinnamoyloxazolidin-2 -ones on the Stability of the Intermediate Adduct-radical, Electrophilicity of the Adding Radicals and the Conditions for their Generation. J. Chem. Soc., Perkin Trans. 1 1997, 3101-3106.
72. Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J.; Miyashiro, J. M.; Rowell, B. W.; Yu, S. S. Improved procedure for the reduction of N-acyloxazolidinones. Synth. Commun. 1990, 20, 307-312. For preparation, see Tararov, V. I.; Kuznetznov, N. Y.; Bakhmutov, V. I.; Ikonnikov, T. F.; Bubnov, Y. N.; Khrustalev, V. N.; Saveleva, T. F.; Belokon, Y. N. Remarkable Dependence of the Regioselectivity of Free Radical Additions to 3-Cinnamoyloxazolidin-2 -ones on the Stability of the Intermediate Adduct-radical, Electrophilicity of the Adding Radicals and the Conditions for their Generation. J. Chem. Soc., Perkin Trans. 1 1997, 3101-3106.
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74. The synthesis of compound (+)-28 has been reported using different reaction conditions: Wu, M. J.; Wu, C. C.; Lee, P.-C. Lewis acid promoted asymmetric 1,4-addition of allyltrimethylsilanes to chiral α,β-unsaturated N-acylamides. Tetrahedron Lett. 1992, 33, 2547-2548.
75. Attempts to affect this transformation with the N-Boc-protected lactam did not yield any desired pyrrolinone, possibly due to the competitive cyclization of the metalloimine onto the lactam carbonyl.
76. 12 with crystal unit cell constants a = 57.98 Å, b = 87.53 Å, and c = 46.29 Å. The structure was refined with XPLOR using data between 2 and 6 Å resolution yielding a final R factor of 0.210. This structure has been deposited with the Protein Data Bank with access number 1NPV.
77. Overlays were done with the Insight II software program (Molecular Simulations Inc.). The RMS values were generated by automatically overlaying all of the protease atoms from one protease-inhibitor complex with the protease atoms from another complex and are as follows: indanol (-)-7/Indinavir = 0.738; carbamate (-)-23/Indinavir = 0.677; lactam (+)-24/ Indinavir = 0.934; indanol (-)-7/carbamate (-)-23 = 0.577; indanol (-)-7/lactam (+)-24 = 0.702; carbamate (-)-23/lactam (+)-24 = 0.651. We also calculated RMS values after overlaying only the flap region of the proteases interacting with the P2 side chain (residues 44-56) where the most significant changes were observed. The RMS values are as follows: indanol (-)-7/ Indinavir = 0.834; carbamate (-)-23/Indinavir = 0.746; lactam (+)-24/Indinavir = 2.912; indanol (-)-7/carbamate (-)-23 = 0.454; indanol (-)-7/lactam (+)-24 = 2.916; carbamate (-)-23/ lactam (+)-24 = 2.867.
78. Heefner, D. L. Unpublished results, Sepracor Inc., Marlborough, MA.