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Bioorganic & Medicinal Chemistry Letters
Volume 4, Issue 10
19 May 1994
Pages 1191-1194

PII: S0960-894X(01)80327-9
Copyright © 1994 Published by Elsevier Science Ltd. All rights reserved.

Inhibition of human immunodeficiency virus-1 protease by a C2-symmetrical phosphinic acid amide

Anusch Peyman, *a, Konrad Wagnera, Karl-Heinz Budta, Jörg Spaniga, Dieter Rupperta, Christoph Meichsnera and Arno Paessensb

a Hoechst AG, PharmaResearch, 65926 Frankfurt, FRG
b Institute of Virology, Pharma Research Center, 42096 Wuppertal, FRG

Received 6 January 1994.  Available online 6 March 2001.


The inhibition of HIV protease with C2-symmetric phosphinic acid based inhibitors is independent of the dissociation grade of the phosphinic acid. The corresponding amides are not only good inhibitors of HIV protease but also inhibit HIV replication in vitro because of their increased lipophilicity.

Graphical Abstract

C2-symmetric Phosphinic acid amides are good inhibitors of HIV protease and also inhibit HIV replication in vivo due to increased lipophilicity as compared to the free acids.



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The use of a phosphinic acid amide as an enzyme inhibitor (of pepsin) has so far only been described once by P.A. Bartlett and F. Acher Bull. Chem. Soc. France (1986), p. 771 They used a slightly different synthesis by first converting the phosphinic acid to phosphinic azides, followed by ammonolysis. . 

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pHA and IL-2 stimulated peripheral blood lymphocytes (PBL's) were infected with HIV-1 D34 isolate by pellet infection and incubated in the presence of diluted test compound for 3¯8 days at 37 °C. Viral replication was evaluated by light microscopiy for syncytia formation and detection of viral p24 capture assay (Vironostika HIV, Organon Teknika).

The phosphinic acid amides are only pseudo-C2-symmetric, however, they could be subject to pseudo-rotation ( does show only one signal in 31P-NMR at 34,2 ppm).

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