Piperidine renin inhibitors: from leads to drug candidates

• Published in: Farmaco (Società chimica italiana : 1989) 2001-01, Vol.56 (1), p.21-27
• Main Authors: Märki, H.P., Binggeli, A., Bittner, B., Bohner-Lang, V., Breu, V., Bur, D., Coassolo, Ph, Clozel, J.P., D'Arcy, A., Doebeli, H., Fischli 1, W., Funk, Ch, Foricher, J., Giller, T., Grüninger, F., Guenzi, A., Güller, R., Hartung, T., Hirth, G., Jenny, Ch, Kansy, M., Klinkhammer, U., Lave, T., Lohri, B., Luft, F.C., Mervaala, E.M., Müller, D.N., Müller, M., Montavon, F., Oefner, Ch, Qiu, C., Reichel, A., Sanwald-Ducray, P., Scalone, M., Schleimer, M., Schmid, R., Stadler, H., Treiber 1, A., Valdenaire 2, O., Vieira, E., Waldmeier, P., Wiegand-Chou, R., Wilhelm, M., Wostl, W., Zell, M., Zell, R.
• Format: Article
• Language: English
• Subjects: Animals; Antihypertensive agents; Antihypertensive Agents - pharmacology; Aspartic proteinase; Biological and medical sciences; Blood Pressure - drug effects; Cardiovascular system; Humans; Medical sciences; Pharmacology. Drug treatments; Piperidines - chemical synthesis; Piperidines - pharmacology; Renal Insufficiency - drug therapy; Renin; Renin - antagonists & inhibitors; Renin - pharmacology; Renin-inhibitor
• ISSN: 0014-827X; 1879-0569
• DOI: 10.1016/S0014-827X(01)01004-7

Non-peptidomimetic renin inhibitors of the piperidine type represent a novel structural class of compounds potentially free of the drawbacks seen with peptidomimetic compounds so far. Synthetic optimization in two structural series focusing on improvement of potency, as well as on physicochemical properties and metabolic stability, has led to the identification of two candidate compounds 14 and 23. Both display potent and long-lasting blood pressure lowering effects in conscious sodium-depleted marmoset monkeys and double transgenic rats harboring both the human angiotensinogen and the human renin genes. In addition, 14 normalizes albuminuria and kidney tissue damage in these rats when given over a period of 4 weeks. These data suggest that treatment of chronic renal failure patients with a renin inhibitor might result in a significant improvement of the disease status.