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

  • ACS Med Chem Lett. 2016 May 9;7(7):702-7. doi: 10.1021/acsmedchemlett.6b00135.
Christopher J Bungard  1 Peter D Williams  1 Jeanine E Ballard  1 David J Bennett  1 Christian Beaulieu  2 Carolyn Bahnck-Teets  1 Steve S Carroll  1 Ronald K Chang  1 David C Dubost  1 John F Fay  1 Tracy L Diamond  1 Thomas J Greshock  1 Li Hao  3 M Katharine Holloway  1 Peter J Felock  1 Jennifer J Gesell  1 Hua-Poo Su  1 Jesse J Manikowski  1 Daniel J McKay  2 Mike Miller  1 Xu Min  1 Carmela Molinaro  1 Oscar M Moradei  2 Philippe G Nantermet  1 Christian Nadeau  2 Rosa I Sanchez  1 Tummanapalli Satyanarayana  3 William D Shipe  1 Sanjay K Singh  3 Vouy Linh Truong  2 Sivalenka Vijayasaradhi  3 Catherine M Wiscount  1 Joseph P Vacca  2 Sheldon N Crane  2 John A McCauley  1
Affiliations
  • 1. Merck Research Laboratories , 770 Sumneytown Pike, PO Box 4, West Point, Pennsylvania 19486, United States.
  • 2. Merck Frosst Centre for Therapeutic Research , 16711 TransCanada Highway, Kirkland, Quebec H9H 3L1, Canada.
  • 3. Albany Molecular Research Singapore Research Center , 61 Science Park Road #05-01, The Galen Singapore Science Park II, Singapore 117525.
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.

Keywords
HIV; MK-8718; inhibitor; protease.
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