导致高效HIV-1蛋白酶抑制剂的哌嗪磺酰胺核心结构的设计与合成
Design and Synthesis of Piperazine Sulfonamide Cores Leading to Highly Potent HIV-1 Protease Inhibitors.
作者信息
Bungard Christopher J, Williams Peter D, Schulz Jurgen, Wiscount Catherine M, Holloway M Katharine, Loughran H Marie, Manikowski Jesse J, Su Hua-Poo, Bennett David J, Chang Lehua, Chu Xin-Jie, Crespo Alejandro, Dwyer Michael P, Keertikar Kartik, Morriello Gregori J, Stamford Andrew W, Waddell Sherman T, Zhong Bin, Hu Bin, Ji Tao, Diamond Tracy L, Bahnck-Teets Carolyn, Carroll Steven S, Fay John F, Min Xu, Morris William, Ballard Jeanine E, Miller Michael D, McCauley John A
机构信息
Merck & Co., Inc., 770 Sumneytown Pike, PO Box 4, West Point, Pennsylvania 19486, United States.
Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
出版信息
ACS Med Chem Lett. 2017 Nov 13;8(12):1292-1297. doi: 10.1021/acsmedchemlett.7b00386. eCollection 2017 Dec 14.
Abstract
Using the HIV-1 protease binding mode of and 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 .
摘要
以[具体药物1]和[具体药物2]的HIV-1蛋白酶结合模式为灵感，设计并合成了一种新型的含天冬氨酸结合的双环哌嗪磺酰胺核心结构。相对于[对比药物]，含有该核心结构的HIV-1蛋白酶抑制剂的酶结合亲和力提高了60倍，抗病毒活性提高了10倍。
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本文引用的文献
1
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. eCollection 2016 Jul 14.
2
Investigational protease inhibitors as antiretroviral therapies.
Expert Opin Investig Drugs. 2016 Oct;25(10):1189-200. doi: 10.1080/13543784.2016.1212837. Epub 2016 Aug 2.
3
Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS.
J Med Chem. 2016 Jun 9;59(11):5172-208. doi: 10.1021/acs.jmedchem.5b01697. Epub 2016 Jan 22.
4
Regioselective ring-opening of amino acid-derived chiral aziridines: an easy access to cis-2,5-disubstituted chiral piperazines.
Chem Asian J. 2011 Jan 3;6(1):189-97. doi: 10.1002/asia.201000554.
5
Expedite protocol for construction of chiral regioselectively N-protected monosubstituted piperazine, 1,4-diazepane, and 1,4-diazocane building blocks.
J Org Chem. 2009 Aug 7;74(15):5652-5. doi: 10.1021/jo900441s.
6
PL-100, a novel HIV-1 protease inhibitor displaying a high genetic barrier to resistance: an in vitro selection study.
J Med Virol. 2008 Dec;80(12):2053-63. doi: 10.1002/jmv.21329.
7
Active human immunodeficiency virus protease is required for viral infectivity.
Proc Natl Acad Sci U S A. 1988 Jul;85(13):4686-90. doi: 10.1073/pnas.85.13.4686.
8
Cleavage of HIV-1 gag polyprotein synthesized in vitro: sequential cleavage by the viral protease.
AIDS Res Hum Retroviruses. 1989 Dec;5(6):577-91. doi: 10.1089/aid.1989.5.577.
9
Structure at 2.5-A resolution of chemically synthesized human immunodeficiency virus type 1 protease complexed with a hydroxyethylene-based inhibitor.
Biochemistry. 1991 Feb 12;30(6):1600-9. doi: 10.1021/bi00220a023.
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