Synthesis and Antiviral Activity of a Series of HIV-1 Protease Inhibitors with Functionality Tethered to the P1 or P1′ Phenyl Substituents: X-ray Crystal Structure Assisted Design

Wayne J. Thompson; Paula M.D. Fitzgerald; M. Katharine Holloway; Emilio A. Emini; Paul L. Darke; Brian M. McKeever; William A. Schleif; Julio C. Quintero; Joan A. Zugay; Thomas J. Tucker; John E. Schwering; Carl F. Homnick; Jack Nunberg; James P. Springer; Joel R. Huff

doi:10.1021/jm00088a003

Synthesis and Antiviral Activity of a Series of HIV-1 Protease Inhibitors with Functionality Tethered to the P₁ or P₁′ Phenyl Substituents: X-ray Crystal Structure Assisted Design

Wayne J. Thompson, Paula M.D. Fitzgerald, M. Katharine Holloway, Emilio A. Emini, Paul L. Darke, Brian M. McKeever, William A. Schleif, Julio C. Quintero, Joan A. Zugay, Thomas J. Tucker, John E. Schwering, Carl F. Homnick, Jack Nunberg, James P. Springer, Joel R. Huff

Montana Biotechnology Center

Merck

Research output: Contribution to journal › Article › peer-review

199 Scopus citations

Abstract

By tethering of a polar hydrophilic group to the P₁ or P₁′ substituent of a Phe-based hydroxyethylene isostere, the antiviral potency of a series of HIV protease inhibitors was improved. The optimum enhancement of anti-HIV activity was observed with the 4-morpholinylethoxy substituent. The substituent effect is consistent with a model derived from inhibitor docked in the crystal structure of the native enzyme. An X-ray crystal structure of the inhibited enzyme determined to 2.25 Å verifies the modeling predictions.

Original language	English
Pages (from-to)	1685-1701
Number of pages	17
Journal	Journal of Medicinal Chemistry
Volume	35
Issue number	10
DOIs	https://doi.org/10.1021/jm00088a003
State	Published - May 1 1992

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Thompson, W. J., Fitzgerald, P. M. D., Holloway, M. K., Emini, E. A., Darke, P. L., McKeever, B. M., Schleif, W. A., Quintero, J. C., Zugay, J. A., Tucker, T. J., Schwering, J. E., Homnick, C. F., Nunberg, J., Springer, J. P., & Huff, J. R. (1992). Synthesis and Antiviral Activity of a Series of HIV-1 Protease Inhibitors with Functionality Tethered to the P₁ or P₁′ Phenyl Substituents: X-ray Crystal Structure Assisted Design. Journal of Medicinal Chemistry, 35(10), 1685-1701. https://doi.org/10.1021/jm00088a003

@article{911557b08535426f8f9bf80809aab0df,

title = "Synthesis and Antiviral Activity of a Series of HIV-1 Protease Inhibitors with Functionality Tethered to the P1 or P1′ Phenyl Substituents: X-ray Crystal Structure Assisted Design",

abstract = "By tethering of a polar hydrophilic group to the P1 or P1′ substituent of a Phe-based hydroxyethylene isostere, the antiviral potency of a series of HIV protease inhibitors was improved. The optimum enhancement of anti-HIV activity was observed with the 4-morpholinylethoxy substituent. The substituent effect is consistent with a model derived from inhibitor docked in the crystal structure of the native enzyme. An X-ray crystal structure of the inhibited enzyme determined to 2.25 {\AA} verifies the modeling predictions.",

author = "Thompson, {Wayne J.} and Fitzgerald, {Paula M.D.} and Holloway, {M. Katharine} and Emini, {Emilio A.} and Darke, {Paul L.} and McKeever, {Brian M.} and Schleif, {William A.} and Quintero, {Julio C.} and Zugay, {Joan A.} and Tucker, {Thomas J.} and Schwering, {John E.} and Homnick, {Carl F.} and Jack Nunberg and Springer, {James P.} and Huff, {Joel R.}",

year = "1992",

month = may,

day = "1",

doi = "10.1021/jm00088a003",

language = "English",

volume = "35",

pages = "1685--1701",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

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Thompson, WJ, Fitzgerald, PMD, Holloway, MK, Emini, EA, Darke, PL, McKeever, BM, Schleif, WA, Quintero, JC, Zugay, JA, Tucker, TJ, Schwering, JE, Homnick, CF, Nunberg, J, Springer, JP & Huff, JR 1992, 'Synthesis and Antiviral Activity of a Series of HIV-1 Protease Inhibitors with Functionality Tethered to the P₁ or P₁′ Phenyl Substituents: X-ray Crystal Structure Assisted Design', Journal of Medicinal Chemistry, vol. 35, no. 10, pp. 1685-1701. https://doi.org/10.1021/jm00088a003

Synthesis and Antiviral Activity of a Series of HIV-1 Protease Inhibitors with Functionality Tethered to the P₁ or P₁′ Phenyl Substituents: X-ray Crystal Structure Assisted Design. / Thompson, Wayne J.; Fitzgerald, Paula M.D.; Holloway, M. Katharine et al.
In: Journal of Medicinal Chemistry, Vol. 35, No. 10, 01.05.1992, p. 1685-1701.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Synthesis and Antiviral Activity of a Series of HIV-1 Protease Inhibitors with Functionality Tethered to the P1 or P1′ Phenyl Substituents

T2 - X-ray Crystal Structure Assisted Design

AU - Thompson, Wayne J.

AU - Fitzgerald, Paula M.D.

AU - Holloway, M. Katharine

AU - Emini, Emilio A.

AU - Darke, Paul L.

AU - McKeever, Brian M.

AU - Schleif, William A.

AU - Quintero, Julio C.

AU - Zugay, Joan A.

AU - Tucker, Thomas J.

AU - Schwering, John E.

AU - Homnick, Carl F.

AU - Nunberg, Jack

AU - Springer, James P.

AU - Huff, Joel R.

PY - 1992/5/1

Y1 - 1992/5/1

N2 - By tethering of a polar hydrophilic group to the P1 or P1′ substituent of a Phe-based hydroxyethylene isostere, the antiviral potency of a series of HIV protease inhibitors was improved. The optimum enhancement of anti-HIV activity was observed with the 4-morpholinylethoxy substituent. The substituent effect is consistent with a model derived from inhibitor docked in the crystal structure of the native enzyme. An X-ray crystal structure of the inhibited enzyme determined to 2.25 Å verifies the modeling predictions.

AB - By tethering of a polar hydrophilic group to the P1 or P1′ substituent of a Phe-based hydroxyethylene isostere, the antiviral potency of a series of HIV protease inhibitors was improved. The optimum enhancement of anti-HIV activity was observed with the 4-morpholinylethoxy substituent. The substituent effect is consistent with a model derived from inhibitor docked in the crystal structure of the native enzyme. An X-ray crystal structure of the inhibited enzyme determined to 2.25 Å verifies the modeling predictions.

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U2 - 10.1021/jm00088a003

DO - 10.1021/jm00088a003

M3 - Article

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AN - SCOPUS:0026627809

SN - 0022-2623

VL - 35

SP - 1685

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JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 10

ER -

Synthesis and Antiviral Activity of a Series of HIV-1 Protease Inhibitors with Functionality Tethered to the P₁ or P₁′ Phenyl Substituents: X-ray Crystal Structure Assisted Design

Abstract

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