Renin Inhibitors. Dipeptide Analogues of Angiotensinogen Utilizing a Dihydroxyethylene Transition-State Mimic at the Scissile Bond To Impart Greater Inhibitory Potency

Article abstract of DOI:10.1021/jm00120a005

The synthesis of diol-containing inhibitors has revealed that a simple vicinal diol functionality corresponding to the scissile Leu-Val bond in human angiotensinogen is capable of imparting inhibitory activity at a comparable or higher level than either the corresponding aldehyde or hydroxymethyl functionality (compare inhibitors 2a-c or 3a-c).This finding has lead to the further optimization of a series of small transition-state analogue inhibitors by the inclusion of a second hydroxyl group in the Leu-Val surrogate to give compounds that inhibited human renin in the 200-700-pM range (e.g. 43, 45, 63, 66).The magnitude of effect of the second hydroxyl group on potency is not only dictated by the absolute stereochemistry of the diol but also by the side chain of the P₁ residue.Molecular modeling of the diol-containing inhibitors suggests that one of the hydroxyl groups hydrogen bonds to Asp 32 and Asp 215, while the second hydrogen bonds to Asp 215.These diol inhibitors are extremely selective for human renin over the related enzymes cathepsin D, pepsin, and gastricsin.At high concentrations, compounds containing a leucine or phenylalanine rather than a histidine at the P₂ position gave only minor amounts of inhibition of the other enzymes.Inhibitor 43 suppressed plasma renin activity completely and lowered mean blood pressure in monkeys after both intravenous and intraduodenal administration, but the blood pressure drop lasted les than 1 h.Monitoring the blood levels of 43 by enzyme inhibition assay after intraduodenal administration to monkeys or oral administration to rats revealed low absorption and rapid clearance.While intratracheal administration to dogs gave approximately 50percent bioavailability, rapid clearance was still a problem.After examination of inhibitor 45 in a sensitive primate model in which monkeys were rendered both hypertensive and hyperreninemic, the effects on lowering systolic but not diastolic pressure were apparent even after 22 h postdosing.Details on the synthesis, in vitro structure-activity relationships, molecular modeling, in vivo activity, and metabolism of these inhibitors are described.