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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