Renin inhibitors

Abstract

Since the early 1980s, an intensive effort has been focused on the development of orally effective and long-acting inhibitors of renin. During this time, in vitro potency has increased greatly, with several transition-state inhibitor designs yielding inhibitors with subnanomolar IC50 values. In the meantime, both the molecular weight and peptide character of the inhibitors has decreased as important binding elements have been focused into smaller and more stable structures. The resulting inhibitors have shown promising activities in several in vivo models and (in two cases) in man. Nevertheless, renin inhibitors reported to date have limited oral bioavailability and short duration of action, and improvements in both will be necessary for them to compete effectively with ACE inhibitors. Renin inhibitors which have entered clinical studies have at least one naturally occurring amino acid and three or more amide bonds. It is reasonable to expect that continued development will produce wholly nonpeptide inhibitors with still lower MW, and it may be these "second-generation" inhibitors which will succeed as therapeutic agents. Development of orally effective and long-acting inhibitors of renin will enable their long-term antihypertensive efficacy and possible advantages over ACE inhibitor to be investigated.

Structure‐based subsite specificity mapping of human cathepsin D using statine‐based inhibitors

“…Aganval and Rich (1 986 cathepsin D was included in studies on inhibition of human aspartic proteases using human renin inhibitors (Greenlee, 1990;Jupp et al, 1990;Rao et al, 1993). The subsite specificity of human cathepsin D was mapped using a series of synthetic peptide substrates combined with a model of the enzyme .…”

“…Recently, mice with a deletion of the cathepsin D gene were shown to exhibit developmental abnormalities in intestinal and lymphoid tissue (Saftig et al, 1995). These studies all point to important physiological roles for this enzyme, and suggest that human cathepsin D may be a target of therapeutic significance.Aganval and Rich (1 986 cathepsin D was included in studies on inhibition of human aspartic proteases using human renin inhibitors (Greenlee, 1990;Jupp et al, 1990;Rao et al, 1993). The subsite specificity of human cathepsin D was mapped using a series of synthetic peptide substrates combined with a model of the enzyme .…”

Protein binding of human immunodeficiency virus protease inhibitor KNI-272 and alteration of its in vitro antiretroviral activity in the presence of high concentrations of proteins

“…Indeed, one such compound, dextran sulfate, has failed to exert its otherwise potent antiretroviral activity when given to patients with advanced HIV-1 infection upon both oral and intravenous administrations (1,10,16). Moreover, a number of renin inhibitors which, like KNI-272, also represent peptide-based agents, showed markedly reduced activity in enzymatic assays performed in the presence of high concentrations of human plasma, while such agents exhibited potent inhibition in pure enzymatic assays involving no plasma proteins (11). In certain cases, the high potency of certain renin inhibitors in pure enzymatic assays has been considered an artifact of assay conditions (4).…”

SDZ PRI 053, an orally bioavailable human immunodeficiency virus type 1 proteinase inhibitor containing the 2-aminobenzylstatine moiety

“…Unfortunately, rational drug design of HIV proteinase inhibitors currently is not able to precisely define parameters of molecules which would predict their oral bioavailability. For peptidic compounds, such as most HIV proteinase inhibitors, only general guidelines have been deduced: reduction of size, elimination of as many peptide bonds as possible, and adequate balance between hydrophobic and hydrophilic character are expected to lead to derivatives with enhanced oral absorption (18).…”