Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 2. Peptide structure- activity studies

Journal of Medicinal Chemistry

Volumn 41, Issue 15, 1998, Pages 2819-2834

  Dragovich, Peter S ^a   Webber, Stephen E ^a   Babine, Robert E ^a   Fuhrman, Sheila A ^a   Patick, Amy K ^a   Matthews, David A ^a   Reich, Siegfried H ^a   Marakovits, Joseph T ^a   Prins, Thomas J ^a   Zhou, Ru ^a   Tikhe, Jayashree ^a   Littlefield, Ethel S ^a   Bleckman, Ted M ^a   Wallace, Michael B ^a   Little, Thomas L ^a   Ford, Clifford E ^a   Meador III, James W ^a   Ferre, Rose Ann ^a   Brown, Edward L ^a   Binford, Susan L ^a   DeLisle, Dorothy M ^a   Worland, Stephen T ^a   more..

^a AGOURON PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIVIRUS AGENT; CYSTEINE PROTEINASE INHIBITOR;

ANTIVIRAL ACTIVITY; ARTICLE; DRUG CONFORMATION; DRUG POTENCY; DRUG SYNTHESIS; HUMAN RHINOVIRUS; NONHUMAN; PROTEINASE INHIBITION; STRUCTURE ACTIVITY RELATION; VIRUS INHIBITION;

ANTIVIRAL AGENTS; BINDING SITES; CELL LINE, TRANSFORMED; CRYSTALLOGRAPHY, X-RAY; CYSTEINE ENDOPEPTIDASES; CYSTEINE PROTEINASE INHIBITORS; DRUG DESIGN; DRUG EVALUATION, PRECLINICAL; HUMANS; OLIGOPEPTIDES; RHINOVIRUS; STRUCTURE-ACTIVITY RELATIONSHIP; VIRAL PROTEINS;

EID: 15144354736     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9800696     Document Type: Article

References (61)

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18. In the discussion of the X-ray crystal structure, the notation "3CP" indicates 3C protease derived from HRV-2 unless otherwise specified. This protein provided diffraction quality crystals more routinely than the serotype 14-derived protease. The inhibitor-binding regions of the two enzymes do not differ significantly: Matthews, D. A.; et al. manuscript in preparation.
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31. The preparation of ketone 113 from N-α-Boc-L-glutamic acid α-benzyl ester has not been optimized.
32. 24
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38. 2O) and subsequent debenzylation provided the carboxylic acid (not shown) required for the preparation of compound 32.
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40. 24
41. 31
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44. 4.
45. 4.
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47. 3, i-PrOH.
48. The tert-butyl esters of the amino acids required for the preparation of 61 and 62 were synthesized by the reductive coupling of morpholine with the aldehydes derived from N-α-Cbz-L-aspartic acid α-tert-butyl ester and N-α-Cbz-L-glutamic acid α-tert-butyl ester, respectively. See: (a) Valerio, R. M.; Alewood, P. F.; Johns, R. B. Synthesis of Optically Active 2-(tert-Butyloxycarbonylamino)-4-dialkoxyphosphorylbutanoate Protected Isosteres of O-Phosphonoserine for Peptide Synthesis. Synthesis 1988, 786-789. (b) Faust, J.; Schreiber, K. Der Normalisierungsfaktor für die Tomatenmutante chloronerva; Synthese des (S)-Piperidin-2-carbonsäureanalogons von Nicotianamin. Z. Chem. 1989, 29, 20-21. The free carboxylic acids were prepared by treatment of the tert-butyl esters with TFA.
49. The tert-butyl esters of the amino acids required for the preparation of 61 and 62 were synthesized by the reductive coupling of morpholine with the aldehydes derived from N-α-Cbz-L-aspartic acid α-tert-butyl ester and N-α-Cbz-L-glutamic acid α-tert-butyl ester, respectively. See: (a) Valerio, R. M.; Alewood, P. F.; Johns, R. B. Synthesis of Optically Active 2-(tert-Butyloxycarbonylamino)-4-dialkoxyphosphorylbutanoate Protected Isosteres of O-Phosphonoserine for Peptide Synthesis. Synthesis 1988, 786-789. (b) Faust, J.; Schreiber, K. Der Normalisierungsfaktor für die Tomatenmutante chloronerva; Synthese des (S)-Piperidin-2-carbonsäureanalogons von Nicotianamin. Z. Chem. 1989, 29, 20-21. The free carboxylic acids were prepared by treatment of the tert-butyl esters with TFA.
50. 2O).
51. 2N-L-LeU-OtBu·HCl and subsequent acidic deprotection (TFA).
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53. 3) and subsequent acidic deprotection (TFA).
54. 2O).
55. 4NF) provided the desired dipeptide.
56. 2, Pd/C; (ii) CbzCl, 4-methylmorpholine; (iii) TFA.
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58. 2, Pd/C).
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