title: A new class of orally active glycol renin inhibitors containing phenyllactic acid at P3.
abstract: We prepared a new series of renin inhibitors based on dipeptide glycols, replacing the P4-P3 subsites with an O-(N-morpholinocarbonyl)-3-L-phenyllactic acid residue. This modification proved bioisosteric with Boc-L-phenylalanine, giving rise to highly potent human renin inhibitors (1-5 nM), e.g., SC-46944 (IC50 = 5 nM). Moreover, this change produced compounds that are orally efficacious in reducing plasma renin activity in salt-depleted marmosets.
authors.affiliation: G.D. Searle and Co. Skokie, Ill. 60077.
authors.forename: G J
authors.initials: GJ
authors.lastname: Hanson
authors.forename: J S
authors.initials: JS
authors.lastname: Baran
authors.forename: H S
authors.initials: HS
authors.lastname: Lowrie
authors.forename: M A
authors.initials: MA
authors.lastname: Russell
authors.forename: S J
authors.initials: SJ
authors.lastname: Sarussi
authors.forename: K
authors.initials: K
authors.lastname: Williams
authors.forename: M
authors.initials: M
authors.lastname: Babler
authors.forename: S E
authors.initials: SE
authors.lastname: Bittner
authors.forename: S E
authors.initials: SE
authors.lastname: Papaioannou
authors.forename: P C
authors.initials: PC
authors.lastname: Yang
mesh_terms: D000818:Animals; D002143:Callitrichinae; D004151:Dipeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D006018:Glycols / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D007773:Lactates; D008968:Molecular Conformation; D015394:Molecular Structure; D009025:Morpholines / Q000494:pharmacology; D012083:Renin / Q000097:blood; D000092502:Renin Inhibitors
chemical_list: D004151:Dipeptides; D006018:Glycols; D007773:Lactates; D009025:Morpholines; D012083:Renin; D000092502:Renin Inhibitors; C059279:O-(N-morpholinocarbonyl)-3-phenyllactic acid; C059277:SC 46944