Dieter Ruppert

New hybrid transition state analog inhibitors of HIV protease with peripheric C2-symmetry

Abstract The snythesis of novel hybrid transition state analogs, a combination of phosphinic acid- and hydroxy-methylene-type inhibitors of HIV protease, is demonstrated. These nonsymmetrical structures, placed in a peripheric C 2 -symmetrical environment, inhibit HIV protease in the lower nanomolar range.

C2-symmetric phosphinic acid inhibitors of HIV protease

Abstract The synthesis of the previously not accessible symmetrical bis(α-aminoalkyl)phosphinic acids is demonstrated. These compounds are valuable central building blocks in the synthesis of HIV protease inhibitors.

Non-peptide-based inhibitors of human immunodeficiency virus-1 protease

Abstract The use of bis(α-aminoalkyl)phosphinic acids as analogs of the tetrahedral intermediate formed on the path to peptide hydrolysis in combination with a mimic for a structural water, which is found in HIV protease inhibitor complexes, leads to potent inhibitors of HIV-1 protease.

HIV protease inhibitor HOE/BAY 793, structure-activity relationships in a series of C2-symmetric diols.

A detailed structure-activity relationship of C2-symmetric diol inhibitors of HIV-1 protease leads to inhibitor 6 (HOE/BAY 793) which is outstanding in the inhibition of the enzyme and in the inhibition of viral replication in HIV infected cell culture (IC50: 0.3 nM; EC50: 3 nM). There are well defined steric requirements for the design of the side chains P1-P3 of the inhibitors. In addition, all three side chains need to be lipophilic. While the enzyme tolerates hydrophilic substituents in some cases, drastic reductions in anti-HIV activity are observed in cell culture, most likely due to insufficient cell penetration.

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

Abstract 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.

Structure-activity relationships in a series of C2-symmetric HIV-protease inhibitors

Publisher Summary This chapter describes a series of inhibitors in which a central building block, containing a transition-state mimetic and the P1 and P1’ residues of the HIV-PR cleavage site, is placed in a C 2 -symmetrical peptidic environment and it presents a detailed structure-activity relationship (SAR) for both enzyme inhibition and in vitro activity. The synthesis of the symmetric diamino diol moiety of HOE/BAY 793 is accomplished either by reductive pinacol coupling of N-protected phenylalaninal with SmI 2 or using a mannitol-based bisepoxide which is reacted with (C 6 H 5 ) 2 CuLi. Starting from this central building block, the side chains containing P2, P2’, P3, P3’ are introduced using standard peptide chemistry. These prodrugs release HOE/BAY 793 in a cyclization reaction, which is either only chemically driven or which can be preceded by an enzymatic cleavage. Regarding the inhibition of HIV-PR the phosphinic acid containing inhibitors behave very similar to the diol containing inhibitors with respect to the filling of the P1, P2, and P3 sites.