1. Discovery of MK-8718, an HIV Protease Inhibitor Containing a Novel Morpholine Aspartate Binding Group
- Author
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Li Hao, Carolyn Bahnck-Teets, Catherine M. Wiscount, Daniel J. McKay, Carmela Molinaro, Ronald K. Chang, S S Carroll, Sivalenka Vijayasaradhi, Philippe G. Nantermet, Sanjay Kumar Singh, Christopher J. Bungard, Dubost David C, David Jonathan Bennett, Thomas J. Greshock, Hua-Poo Su, Rosa I. Sanchez, Vouy Linh Truong, Xu Min, John F. Fay, Jeanine E. Ballard, John A. McCauley, Christian Beaulieu, M. Katharine Holloway, Joseph P. Vacca, Michael W. Miller, Tummanapalli Satyanarayana, Sheldon Crane, William D. Shipe, Jesse J. Manikowski, Peter D. Williams, Christian Nadeau, Jennifer J. Gesell, Tracy L. Diamond, Peter J. Felock, and Oscar Miguel Moradei
- Subjects
Hydrolase inhibitor ,chemistry.chemical_classification ,Protease ,010405 organic chemistry ,Chemistry ,Stereochemistry ,medicine.medical_treatment ,Organic Chemistry ,Human immunodeficiency virus (HIV) ,010402 general chemistry ,medicine.disease_cause ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,chemistry.chemical_compound ,Aspartate binding ,Enzyme ,Morpholine ,Drug Discovery ,medicine ,Potency ,HIV Protease Inhibitor - 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.
- Published
- 2016