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

200 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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SDG 3 Good Health and Well-being

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10.1021/jm00088a003

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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",

number = "10",

}

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.

UR - https://www.scopus.com/pages/publications/0026627809

U2 - 10.1021/jm00088a003

DO - 10.1021/jm00088a003

M3 - Article

C2 - 1588551

AN - SCOPUS:0026627809

SN - 0022-2623

VL - 35

SP - 1685

EP - 1701

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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