Studies directed toward the design of orally active renin inhibitors. 1. Some factors influencing the absorption of small peptides

Abstract

A systematic evaluation of structure-absorption relationships using a high throughput intraduodenal rat screening model has led to the delineation of a set of structural parameters that appear to govern bioavailability in a series of peptide-based renin inhibitors. Optimum structures, exemplified by 25 and 41, incorporated a single, solubilizing substituent at the C- or N-terminus combined with a lipophilic P2-site residue. Both inhibitors gave unprecedented plasma drug levels upon intraduodenal administration to monkeys, and the calculated bioavailability for 41 (14 +/- 4%) is the highest reported for any peptidic renin inhibitor.

Discovery of Inhibitors of Human Renin with High Oral Bioavailability

“…In the sodium-depleted guinea pig, 35 reduced blood pressure for greater than 5 hours following an oral dose of 10 mg/kg, with a nearly superimposable profile to that of 34. In sodium-depleted marmosets, 35 lowered blood pressure for greater than 5 hours following a 3 mg/kg oral dose, comparing very favorably with the recently reported [1] bioavailable inhibitor A-72,517 (Figure 3). …”

“…This inhibitor also has high oral bioavailability in two primate species (59%, marmoset and >27%, cynomolgus monkey). High primate bioavailability thus distinguishes 35 from two other bioavailable renin inhibitors [1,2]. In the sodium-depleted guinea pig, 35 reduced blood pressure for greater than 5 hours following an oral dose of 10 mg/kg, with a nearly superimposable profile to that of 34.…”

Design of drugs through a consideration of drug metabolism and pharmacokinetics

“…Unfortunately, the properties required for the absorption of compounds with a number of amide links have not been characterised and drug metabolism expertise performs a screening role rather than disposition principles being applied to true drug design. This is exemplified by the use of a high throughput intraduodenal screen applied recently to the search for oral bioavailability in peptide-based renin inhibitors (7). Optimum structures incorporated a solubilizing substituent at the C or N terminus combined with a lipophilic P2-site residue.…”

“…Diclofenac, with ortho substitution in the "head group" aromatic ring (figure 7) is metabolised principally to 4-hydroxydiclofenac by CYP2C9. In man the drug has a short half-life of approximately 1 hour due to the relatively high metabolic (oxidative) clearance.…”

Development and Validation of a Robust QSAR Model For Piperazine and Keto Piperazine Derivatives as Renin Inhibitors

“…More recently, a novel series of renin inhibitors based on the 3, 9-diazabicyclo nonene have been developed [12]. The piperazine and keto piperazine derivatives have been found to be potent, efficacious, oral and good bioavailable renin inhibitors [11,13,14]. In this study, novel quantitative structure-activity relationship models were built to illustrate the magnitude of the physicochemical properties intended for the piperazine and keto piperazine derivatives as renin inhibitors.…”