title: Dual metalloprotease inhibitors: mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidase.
abstract: A series of 7,6- and 7,5-fused bicyclic thiazepinones and oxazepinones were generated and incorporated as conformationally restricted dipeptide surrogates in mercaptoacyl dipeptides. These compounds are potent inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) both in vitro and in vivo. Compound 1a, a 7,6-fused bicyclic thiazepinone, demonstrated excellent blood pressure lowering in a variety of animal models characterized by various levels of plasma renin activity and significantly potentiated urinary sodium, ANP, and cGMP excretion in a cynomolgus monkey assay. On the basis of its potency and duration of action, compound 1a (BMS-186716) was advanced into clinical development for the treatment of hypertension and congestive heart failure.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Robl
authors.forename: C Q
authors.initials: CQ
authors.lastname: Sun
authors.forename: J
authors.initials: J
authors.lastname: Stevenson
authors.forename: D E
authors.initials: DE
authors.lastname: Ryono
authors.forename: L M
authors.initials: LM
authors.lastname: Simpkins
authors.forename: M P
authors.initials: MP
authors.lastname: Cimarusti
authors.forename: T
authors.initials: T
authors.lastname: Dejneka
authors.forename: W A
authors.initials: WA
authors.lastname: Slusarchyk
authors.forename: S
authors.initials: S
authors.lastname: Chao
authors.forename: L
authors.initials: L
authors.lastname: Stratton
authors.forename: R N
authors.initials: RN
authors.lastname: Misra
authors.forename: M S
authors.initials: MS
authors.lastname: Bednarz
authors.forename: M M
authors.initials: MM
authors.lastname: Asaad
authors.forename: H S
authors.initials: HS
authors.lastname: Cheung
authors.forename: B E
authors.initials: BE
authors.lastname: Abboa-Offei
authors.forename: P L
authors.initials: PL
authors.lastname: Smith
authors.forename: P D
authors.initials: PD
authors.lastname: Mathers
authors.forename: M
authors.initials: M
authors.lastname: Fox
authors.forename: T R
authors.initials: TR
authors.lastname: Schaeffer
authors.forename: A A
authors.initials: AA
authors.lastname: Seymour
authors.forename: N C
authors.initials: NC
authors.lastname: Trippodo
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis*; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000627:therapeutic use; D009320:Atrial Natriuretic Factor / Q000652:urine; D002317:Cardiovascular Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D006152:Cyclic GMP / Q000652:urine; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D006333:Heart Failure / Q000188:drug therapy; D006973:Hypertension / Q000188:drug therapy; D008252:Macaca fascicularis; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000138:chemical synthesis* / Q000627:therapeutic use; D051381:Rats; D012083:Renin / Q000097:blood; D012964:Sodium / Q000652:urine; D013841:Thiazepines / Q000138:chemical synthesis* / Q000627:therapeutic use
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D002317:Cardiovascular Agents; D004791:Enzyme Inhibitors; D011725:Pyridines; D013841:Thiazepines; C106266:omapatrilat; D009320:Atrial Natriuretic Factor; D012964:Sodium; D012083:Renin; D015260:Neprilysin; D006152:Cyclic GMP