Dual metalloprotease inhibitors: mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidase.
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.
Robl
J A
JA
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
Sun
C Q
CQ
Stevenson
J
J
Ryono
D E
DE
Simpkins
L M
LM
Cimarusti
M P
MP
Dejneka
T
T
Slusarchyk
W A
WA
Chao
S
S
Stratton
L
L
Misra
R N
RN
Bednarz
M S
MS
Asaad
M M
MM
Cheung
H S
HS
Abboa-Offei
B E
BE
Smith
P L
PL
Mathers
P D
PD
Fox
M
M
Schaeffer
T R
TR
Seymour
A A
AA
Trippodo
N C
NC
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
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