Drug design with a new transition state analog of the hydrated carbonyl: silicon-based inhibitors of the HIV protease

Abstract

In their first evaluation as inhibitors of an aspartic protease, silanediol peptidomimetics have been found to be nearly as potent as currently available pharmaceutical agents, in enzyme and cell protection assays. These neutral, cell-permeable transition state analogs therefore provide a novel foundation for the design of therapeutic agents.

Recent Developments in the Synthesis and Structure of Organosilanols

“…For example, it does not undergo reaction even with refluxing methanol. 7 In view of this poor reactivity, an alternative synthetic procedure has been adopted to prepare (Me 3 Si) 3 CSi(OH) 3 (217). One of the Si-H bonds in 217 can be converted into a Si-I bond by treatment with I 2 in carbontetrachloride to afford the compound (Me 3 Si) 3 CSi(I)(OH)(H) (218).…”

Bioactive Amino Acids, Peptides and Peptidomimetics Containing Silicon

“…C 2 symmetric HIV protease, and was modeled after the corresponding carbinol 45 reported by Merck [47]. Testing of 44, 45 and the commercial HIV protease inhibitor indinavir (not shown) found them to inhibit the enzyme to a similar degree, with K i values of 2.7 nM, 0.38 nM and 0.37 nM, respectively [48]. In addition, IC 90 values for protection of whole cells against HIV infection gave parallel values, indicating that they all penetrated cell membranes to the same degree, thereby demonstrating the drug-like properties of silanediol 44.…”

“…The critical deprotection of diphenylsilane 61 to give the diol 44 was carefully studied with regard to cleavage of both silicon-phenyl bonds and isolation of monomer 44. Pure 44 was most easily isolated by precipitation, in 37 % yield [48]. …”

Molecular Variations Based on Isosteric Replacements

“…The application of this isosterism remains, however, limited. Figure 8.68 shows a silicon-containing hypocholesterolemic squalene epoxidase inhibitor; [228,229] the silicon analog of the α 2 -adrenergic antagonist atipamezole; [230] a highly potent, stable, and CNS-penetrating silatecan; [231] some ACE inhibitors; [232] HIV protease inhibitors; [233] the (R)-sila-analog of the antidepressant venlafaxine; [234] and a trimethylsilylpyrazole as novel inhibitor of p38 MAP kinase [235] (mitogen-activating protein). Silicon is more electropositive than carbon (and even more if compared to oxygen and nitrogen) and the covalent siliconÀcarbon bonds in the sp 3 hybridization state are 20 percent longer than the corresponding carbonÀcarbon bond.…”