title: Synthesis and biological activity of potent, low molecular weight renin inhibitors.
abstract: A series of renin inhibitors containing the dipeptide transition state mimics (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-cyclohexyl hexanoic acid (Cha-psi[CH(OH)CH2]Ala) and (2R,4S,5S)-5-amino-4-hydroxy-2-isopropyl-6-cyclohexyl hexanoic acid (Cha-psi[CH(OH)CH2]Val) were prepared. A structure-activity study, using pseudopeptide (Boc-Phe-His-Leu-psi[CH(OH)CH2]Val-Ile-His-OH) as our lead structure, led to a new series of inhibitors, which correspond to tripeptides and contain no natural amino acids. For example, R,S-Bpma-Ape-Cha-psi[CH(OH)CH2]Ala-NH2 (IC50 = 1.26 nM against human plasma renin at pH 6.0; molecular weight = 564) has only two thirds of the molecular weight but twice the potency of our original lead. This new class of low molecular weight renin inhibitor displays excellent specificity toward human renin versus the related aspartic proteinase pepsin and angiotensin-1-converting enzyme. Examples are given of selected inhibitors showing encouraging evidence for intestinal absorption after intracolonic and oral administration in male Sprague-Dawley rats.
authors.affiliation: Ferring Research Institute, Chilworth Research Centre, Southampton, United Kingdom. jdiaz@ferringr.com
authors.forename: J
authors.initials: J
authors.lastname: Sueiras-Diaz
authors.forename: D M
authors.initials: DM
authors.lastname: Jones
authors.forename: M
authors.initials: M
authors.lastname: Szelke
authors.forename: J
authors.initials: J
authors.lastname: Deinum
authors.forename: L
authors.initials: L
authors.lastname: Svensson
authors.forename: C
authors.initials: C
authors.lastname: Westerlund
authors.forename: M
authors.initials: M
authors.lastname: Sohtell
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002268:Carboxypeptidases / Q000378:metabolism; D043422:Carboxypeptidases A; D002851:Chromatography, High Pressure Liquid; D002918:Chymotrypsin / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D015394:Molecular Structure; D008970:Molecular Weight; D010434:Pepsin A / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000097:blood; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D002268:Carboxypeptidases; D043422:Carboxypeptidases A; D002918:Chymotrypsin; D010434:Pepsin A; D010455:Peptides; D007703:Peptidyl-Dipeptidase A; D011480:Protease Inhibitors; D012083:Renin; D000092502:Renin Inhibitors