Renin inhibition by substituted piperidines: a novel paradigm for the inhibition of monomeric aspartic proteinases?

Background: The aspartic proteinase renin catalyses the first and rate-limi ting step in the conversion of angiotensinogen to the hormone angiotensin t l, and therefore plays an important physiological role in the regulation of blood pressure. Numerous potent peptidomimetic inhibitors of this importan t drug target have been developed, but none of these compounds have progres sed past clinical phase II trials. Limited oral bioavailability or excessiv e production costs have prevented these inhibitors from becoming ne antihyp ertensive drugs. We were interested in developing new nonpeptidomimetic ren in inhibitors. Results: High-throughput screening of the Roche compound library identified a simple 3,4-disubstituted piperidine lead compound. We determined the cry stal structures of recombinant human renin complexed with two representativ es of this new class. Binding of these substituted piperidine derivatives i s accompanied by major induced-fit adaptations around the enzyme's active s ite. Conclusions: The efficient optimisation of the piperidine inhibitors was fa cilitated by structural analysis of the renin active site in two renin-inhi bitor complexes (some of the piperidine derivatives have picomolar affiniti es for renin). These structural changes provide the basis for a novel parad igm for inhibition of monomeric aspartic proteinases.