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Title: Discovery of MK-8718, an HIV Protease Inhibitor Containing a Novel Morpholine Aspartate Binding Group

Abstract

A novel HIV protease inhibitor was designed using a morpholine core as the aspartate binding group. Analysis of the crystal structure of the initial lead bound to HIV protease enabled optimization of enzyme potency and antiviral activity. This afforded a series of potent orally bioavailable inhibitors of which MK-8718 was identified as a compound with a favorable overall profile.

Authors:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1404956
Resource Type:
Journal Article
Resource Relation:
Journal Name: ACS Medicinal Chemistry Letters; Journal Volume: 7; Journal Issue: 7
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 60 APPLIED LIFE SCIENCES

Citation Formats

Bungard, Christopher J., Williams, Peter D., Ballard, Jeanine E., Bennett, David J., Beaulieu, Christian, Bahnck-Teets, Carolyn, Carroll, Steve S., Chang, Ronald K., Dubost, David C., Fay, John F., Diamond, Tracy L., Greshock, Thomas J., Hao, Li, Holloway, M. Katharine, Felock, Peter J., Gesell, Jennifer J., Su, Hua-Poo, Manikowski, Jesse J., McKay, Daniel J., Miller, Mike, Min, Xu, Molinaro, Carmela, Moradei, Oscar M., Nantermet, Philippe G., Nadeau, Christian, Sanchez, Rosa I., Satyanarayana, Tummanapalli, Shipe, William D., Singh, Sanjay K., Truong, Vouy Linh, Vijayasaradhi, Sivalenka, Wiscount, Catherine M., Vacca, Joseph P., Crane, Sheldon N., and McCauley, John A. Discovery of MK-8718, an HIV Protease Inhibitor Containing a Novel Morpholine Aspartate Binding Group. United States: N. p., 2016. Web. doi:10.1021/acsmedchemlett.6b00135.
Bungard, Christopher J., Williams, Peter D., Ballard, Jeanine E., Bennett, David J., Beaulieu, Christian, Bahnck-Teets, Carolyn, Carroll, Steve S., Chang, Ronald K., Dubost, David C., Fay, John F., Diamond, Tracy L., Greshock, Thomas J., Hao, Li, Holloway, M. Katharine, Felock, Peter J., Gesell, Jennifer J., Su, Hua-Poo, Manikowski, Jesse J., McKay, Daniel J., Miller, Mike, Min, Xu, Molinaro, Carmela, Moradei, Oscar M., Nantermet, Philippe G., Nadeau, Christian, Sanchez, Rosa I., Satyanarayana, Tummanapalli, Shipe, William D., Singh, Sanjay K., Truong, Vouy Linh, Vijayasaradhi, Sivalenka, Wiscount, Catherine M., Vacca, Joseph P., Crane, Sheldon N., & McCauley, John A. Discovery of MK-8718, an HIV Protease Inhibitor Containing a Novel Morpholine Aspartate Binding Group. United States. doi:10.1021/acsmedchemlett.6b00135.
Bungard, Christopher J., Williams, Peter D., Ballard, Jeanine E., Bennett, David J., Beaulieu, Christian, Bahnck-Teets, Carolyn, Carroll, Steve S., Chang, Ronald K., Dubost, David C., Fay, John F., Diamond, Tracy L., Greshock, Thomas J., Hao, Li, Holloway, M. Katharine, Felock, Peter J., Gesell, Jennifer J., Su, Hua-Poo, Manikowski, Jesse J., McKay, Daniel J., Miller, Mike, Min, Xu, Molinaro, Carmela, Moradei, Oscar M., Nantermet, Philippe G., Nadeau, Christian, Sanchez, Rosa I., Satyanarayana, Tummanapalli, Shipe, William D., Singh, Sanjay K., Truong, Vouy Linh, Vijayasaradhi, Sivalenka, Wiscount, Catherine M., Vacca, Joseph P., Crane, Sheldon N., and McCauley, John A. 2016. "Discovery of MK-8718, an HIV Protease Inhibitor Containing a Novel Morpholine Aspartate Binding Group". United States. doi:10.1021/acsmedchemlett.6b00135.
@article{osti_1404956,
title = {Discovery of MK-8718, an HIV Protease Inhibitor Containing a Novel Morpholine Aspartate Binding Group},
author = {Bungard, Christopher J. and Williams, Peter D. and Ballard, Jeanine E. and Bennett, David J. and Beaulieu, Christian and Bahnck-Teets, Carolyn and Carroll, Steve S. and Chang, Ronald K. and Dubost, David C. and Fay, John F. and Diamond, Tracy L. and Greshock, Thomas J. and Hao, Li and Holloway, M. Katharine and Felock, Peter J. and Gesell, Jennifer J. and Su, Hua-Poo and Manikowski, Jesse J. and McKay, Daniel J. and Miller, Mike and Min, Xu and Molinaro, Carmela and Moradei, Oscar M. and Nantermet, Philippe G. and Nadeau, Christian and Sanchez, Rosa I. and Satyanarayana, Tummanapalli and Shipe, William D. and Singh, Sanjay K. and Truong, Vouy Linh and Vijayasaradhi, Sivalenka and Wiscount, Catherine M. and Vacca, Joseph P. and Crane, Sheldon N. and McCauley, John A.},
abstractNote = {A novel HIV protease inhibitor was designed using a morpholine core as the aspartate binding group. Analysis of the crystal structure of the initial lead bound to HIV protease enabled optimization of enzyme potency and antiviral activity. This afforded a series of potent orally bioavailable inhibitors of which MK-8718 was identified as a compound with a favorable overall profile.},
doi = {10.1021/acsmedchemlett.6b00135},
journal = {ACS Medicinal Chemistry Letters},
number = 7,
volume = 7,
place = {United States},
year = 2016,
month = 7
}