New Class of Inhibitors Specific for Human Renin

Abstract

Seven active tetrapeptide amides characterized by a C-terminal phenylalanyl aminoadamantane (PheNHAd) sequence, were identified by selective testing for human renin inhibitory activity among compounds with adjacent hydrophobic groups and molecular size equivalent to 3-5 amino acid residues. The new inhibitors were compared with known renin inhibitors (RIP, pepstatin, H-77) and opioid analgesic agents (Met-enkephalin, morphine), with the following results: The new inhibitors were active against human renin (IC50 approximately 10-5M), but inactive against rat renin and pepsin. Although active in opiate receptor binding studies (IC50 approximately 10(-7)M), they were, with few exceptions, inactive in the mouse writhing and hot plate tests for analgesia. SAR studies suggested a separation of the renin inhibitory from the analgesic activity of enkephalin analogs. Preliminary experiments with sodium-depleted rhesus monkeys indicated hypotensive activity for three of the new inhibitors at 3 mg/kg i.v., and RIP at 1 mg/kg. The recently reported clinical hypotensive properties of RIP (Zusman et al., Trans. Assoc. Am. Physicians 96:365, 1983) along with the present comparative studies suggest that the new inhibitors may lead to clinically useful agents.

The Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives

“…In particular, 1-adamantanamine derivatives like 301 (Scheme 44) were found to produce central and peripheral opioid activities. 616 Another study focusing on the development of peptidic inhibitors for human renin 618 reported adamantane substituted peptides that also displayed high affinities to opiate receptors. The 2-adamantylamino derivative 302 displayed an IC 50 of 1.9 · 10 −10 M in a radioligand binding assay using rat brain homogenate.…”