ES-8891, an orally active inhibitor of human renin.

Abstract

A newly synthesized orally active renin inhibitor, jV-morpholinoacetyl-(l-naphthyl)-L-alanyl-(4-thiazolyl)-L-alanyl (3S,4S)-4-amino-3-hydroxy-5-cyclohexylpentanoyl-/i-hexylamide (ES-8891), was found to be a highly potent competitive inhibitor of human renin with an inhibition constant of 1.1 nM. This inhibitor was also active against monkey renin, although there was less inhibition of renin in pig, rabbit, and rat ES-8891 did not inhibit cathepsin D, pepsin, trypsin, chymotrypsin, angiotensin converting enzyme, and urinary kallikrein at a concentration of 10~5 M. A single oral administration of ES-8891 (10 or 30 mg/kg) to conscious, sodium-depleted marmosets caused a dose-related decrease in plasma renin activity and blood pressure. ES-8891 (30 mg/kg) produced an 80% inhibition of plasma renin activity, which lasted for more than 6 hours. Kidney renin messenger RNA was not significantly changed 6 hours after oral administration of ES-8891 (30 mg/kg). A single oral administration of 240 mg ES-8891 to healthy human volunteers (n=6) produced a significant inhibition of plasma renin activity (75% inhibition at 0.5 and 1 hour, 50% inhibition at 2 hours) with a good correlation of plasma levels of ES-8891. There were no significant changes in blood pressure or heart rate, and no adverse effects were observed. These results suggest that ES-8891 is an orally active human renin inhibitor that may be clinically useful. (Hypertension 1990;15:909-913) T he renin-angiotensin system plays an important role in the regulation of blood pressure and in body fluid homeostasis. Inhibitors of angiotensin converting enzyme (ACE) are now widely used in patients with hypertension and congestive heart failure. Since ACE converts angiotensin I to angiotensin II and also hydrolyzes a variety of biologically active peptides, ACE inhibitors are not a specific blocker of the renin-angiotensin system. However, renin acts on angiotensinogen as its only known substrate. Renin inhibitors may block the renin-angiotensin system in a selective manner and would be expected to produce changes of physiological significance in the renin-angiotensin system. Use of renin inhibitors may also reduce the incidence of ACE inhibitor-induced adverse effects, such as dry cough or angioedema, which may be independent of the renin-angiotensin system. Recently, highly potent competitive inhibitors of human renin have been synthesized and have been demonstrated to be effec-

Recent Advances in the Study of Renin and Angiotensinogen Genes: From Molecules to the Whole Body.

“…An angiotensin-converting enzyme inhibitor (captopril) and a selective antagonist directed at the All receptor (DuP 753) (124) reduced the blood pressure in R/A, R/ -, -IA, and -/ mice. However, a human renin-specific inhibitor (ES-8891) (125) reduced the blood pressure only in R/A mice. These results indicate that the increase in blood pressure in R/A mice is due to the reaction between human renin and human angiotensinogen.…”

Σχεδιασμός Και Σύνθεση Μη Πεπτιδικών Μιμητών Της Αγγειοτασίνης ΙΙ Με Αντιυπερτασική Δράση

“…και οι δημιουργοί τους είναι οι: CGP 38560Α[218], Enalkiren[219], Remikiren[220], ES-8891[221].Το συμπέρασμα που έχει εξαχθεί από τις μελέτες των αναστολέων αυτής της κατηγορίας, είναι ότι παρά τη μεγάλη δραστικότητα τους, έχουν πολύπλοκες χημικές δομές (σχήμα Α.4.2) πεπτιδικής φύσης, που τα εμποδίζει μέχρι στιγμής να εξελιχθούν σε ευρέως χρησιμοποιούμενα φάρμακα.Η άποψη ότι οι μη πεπτιδικοί ανταγωνιστές δε θα είχαν τα μειονεκτήματα των αντιστοίχων πεπτιδίων ήταν μια ελκυστική μα απατηλή στρατηγική μέχρι το 1982, όταν ο Furukawa και οι συνεργάτες του[222] ανακάλυψαν μια σειρά τέτοιων ενώσεων, οι σπουδαιότερες από τις οποίες περιέχονται στον παρακάτω πίνακα: Πίνακας Α.4.1: Οι πρώτοι μη πετττιδικοί ανταγωνιστές του υποδοχέα AT ι της Α Π.Οι ενώσεις αυτές αν και χαρακτηρίζονται από χαμηλή δραστικότητα, αποτελούν εκλεκτικούς συναγωνιστικούς ανταγωνιστές του υποδοχέα ΑΤι της Α II με έλλειψη αγωνιστικών ιδιοτήτων[223]. Αυτές οι πρώτες συνθέσεις υπήρξαν το σημείο έναρξης για την ανακάλυψη του losartan, του πρώτου δραστικού και εκλεκτικού ανταγωνιστή του υποδοχέα ΑΤι που κυκλοφόρησε σαν φάρμακο στο εμπόριο από την Εταιρία DuPont με την ονομασία Cozaar.His 6 της AII και η τρίτη αυτή της βουτυλομάδας της 1 με την πλευρική αλυσίδα της Ile 5 της Α II.…”