Palladium-catalyzed diastereoselective synthesis of β,β-diarylpropionic acid derivatives and its application to the total synthesis of ( R )-tolterodine and the enantiomer of a key intermediate for MK-8718

Author: Dapeng Zou ; Yusheng Wu ; Jingya Li ; Yangjie Wu ; Wubin Zhi

Palladium-catalyzed diastereoselective synthesis of optically active β,β-diarylpropionic acid derivatives employing 4-(tert-butyl)oxazolidin-2-one e.g., (S)-4-(tert-butyl)-3-((S)-3-phenyl-3-(o-tolyl)propanoyl)oxazolidin-2-one as the chiral auxiliary under an air atm. in excellent yields with high diastereoselectivity is reported.The catalytic system is applied to the total synthesis of (R)-tolterodine and the enantiomer of a key intermediate for MK-8718.

14 Dec 2017·ACS medicinal chemistry lettersQ3 · MEDICINE

Design and Synthesis of Piperazine Sulfonamide Cores Leading to Highly Potent HIV-1 Protease Inhibitors

Q3 · MEDICINE

Article

Author: Morriello, Gregori J. ; Holloway, M. Katharine ; Loughran, H. Marie ; Fay, John F. ; Schulz, Jurgen ; Diamond, Tracy L. ; Miller, Michael D. ; Keertikar, Kartik ; Carroll, Steven S. ; Morris, William ; Ji, Tao ; Ballard, Jeanine E. ; Bahnck-Teets, Carolyn ; Wiscount, Catherine M. ; Bungard, Christopher J. ; Manikowski, Jesse J. ; Chu, Xin-Jie ; Chang, Lehua ; Min, Xu ; Hu, Bin ; Dwyer, Michael P. ; Su, Hua-Poo ; Waddell, Sherman T. ; Zhong, Bin ; Williams, Peter D. ; Crespo, Alejandro ; Stamford, Andrew W. ; McCauley, John A. ; Bennett, David J.

Using the HIV-1 protease binding mode of MK-8718 and PL-100 as inspiration, a novel aspartate binding bicyclic piperazine sulfonamide core was designed and synthesized. The resulting HIV-1 protease inhibitor containing this core showed an 60-fold increase in enzyme binding affinity and a 10-fold increase in antiviral activity relative to MK-8718.

14 Jul 2016·ACS medicinal chemistry lettersQ3 · MEDICINE

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

Q3 · MEDICINE

Article

Author: Holloway, M Katharine ; McCauley, John A ; Dubost, David C ; Bennett, David J ; Nantermet, Philippe G ; Diamond, Tracy L ; Hao, Li ; Moradei, Oscar M ; Fay, John F ; McKay, Daniel J ; Nadeau, Christian ; Vacca, Joseph P ; Carroll, Steve S ; Bungard, Christopher J ; Sanchez, Rosa I ; Molinaro, Carmela ; Su, Hua-Poo ; Beaulieu, Christian ; Miller, Mike ; Ballard, Jeanine E ; Chang, Ronald K ; Satyanarayana, Tummanapalli ; Min, Xu ; Felock, Peter J ; Truong, Vouy Linh ; Shipe, William D ; Wiscount, Catherine M ; Williams, Peter D ; Gesell, Jennifer J ; Greshock, Thomas J ; Vijayasaradhi, Sivalenka ; Crane, Sheldon N ; Singh, Sanjay K ; Manikowski, Jesse J ; Bahnck-Teets, Carolyn

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.

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Indication	Highest Phase	Country/Location	Organization	Date
HIV Infections	Discovery	United States	Merck & Co., Inc.	14 Jul 2016

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