Studies directed toward the design of orally active renin inhibitors. 2. Development of the efficacious, bioavailable renin inhibitor (2S)-2-benzyl-3-[[(1-methylpiperazin-4-yl)sulfonyl]propionyl]-3-thiazol-4-yl-L-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (A-72517)

Abstract

Employing a set of empirical guidelines for the design of well-absorbed renin inhibitors, we have followed two strategies to improve potency while maintaining bioavailability. One process involved incorporation of an extended N-terminal residue bearing a weakly basic substituent and is exemplified by compound 25. The other approach centered on the inclusion of an N-terminal sulfonamide and culminated in the discovery of inhibitor 32 (A-72517). Both 25 and 32 showed excellent bioavailability in the rat and ferret (> 25%) and, while subject to hepatic elimination in the monkey, were efficacious in this species.

A Bioavailability Score

“…There are examples that consideration of physical properties has been useful in the optimization of the bioavailability or permeability within specific series of compounds. , However, the generalization of such studies to diverse molecules has not been convincingly demonstrated. Indeed, there is no consensus as to the physical properties relevant for bioavailability.…”

Concentration and pH Dependent Aggregation of Hydrophobic Drug Molecules and Relevance to Oral Bioavailability

“…1 Oral bioavailability is defined as the rate and extent of drug molecule absorption into systemic circulation from the gastrointestinal (GI) tract and is governed by the drug and dosage form. [2][3][4] Approximately 40% of drug candidates tested in late-stage clinical trials fail because of low efficacy for reasons including poor bioavailability that can be caused by ineffective intestinal absorption and/or undesirable metabolic activity. [4][5][6] Reliable bioavailability evaluations generally involve testing in animal models and in human subjects, requiring considerable time and expense.…”

“…Oral bioavailability is defined as the rate and extent of drug molecule absorption into systemic circulation from the gastrointestinal (GI) tract and is governed by the drug and dosage form. − Approximately 40% of drug candidates tested in late-stage clinical trials fail because of low efficacy for reasons including poor bioavailability that can be caused by ineffective intestinal absorption and/or undesirable metabolic activity. − Reliable bioavailability evaluations generally involve testing in animal models and in human subjects, requiring considerable time and expense . In vivo systems for bioavailability estimation include monitoring of drug concentrations following intraduodenal dosing in animal models (usually rat or dog) and intestinal perfusion studies in both animals and human subjects. , In vitro test formats include (1) Caco-2 cell monolayers for measurement of compound diffusion rate, − (2) intestinal tissue for permeation measurements, , and (3) immobilized artificial membrane (IAM) chromatography . A number of high-throughput in vitro methods have been designed; however, they are still several orders of magnitude slower than desired and have other limitations as well. − ,,, …”

Diphenylpropionic Acids as New AT1 Selective Angiotensin II Antagonists

“…The success of ACE inhibitors in the treatment of hypertension has increased interest in controlling other targets in the RAS. Substantial effort has gone into finding renin inhibitors, although orally active agents have only recently been reported . Blockade at the receptor level of the effector hormone AII appears to be the most direct way of controlling the RAS.…”