UK-69,578, a novel inhibitor of EC 3.4.24.11 which increases endogenous ANF levels and is natriuretic and diuretic.
A search for potent inhibitors of EC 3.4.24.11, an enzyme which is found most abundantly in the kidney and which degrades atrial natriuretic factor, has led to the identification of UK-69,578. Structure-activity studies starting from substituted N-carboxymethyl dipeptide inhibitors resulted in the introduction of a cyclo-alkane P1' residue and in the replacement of the aza-link between P1 and P1' residues by a methylene group, with a net ten-fold potency gain. UK-69,578 increases endogenous ANF levels and produces natriuretic and diuretic responses intravenously in mice.
Danilewicz
J C
JC
Pfizer Central Research, Sandwich, Kent, United Kingdom.
Barclay
P L
PL
Barnish
I T
IT
Brown
D
D
Campbell
S F
SF
James
K
K
Samuels
G M
GM
Terrett
N K
NK
Wythes
M J
MJ
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood / Q000378:metabolism*; D055598:Chemical Phenomena; D002621:Chemistry; D003509:Cyclohexanecarboxylic Acids; D004232:Diuretics; D006801:Humans; D008297:Male; D051379:Mice; D008871:Microvilli / Q000201:enzymology; D009318:Natriuresis / Q000187:drug effects*; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051381:Rats
D003509:Cyclohexanecarboxylic Acids; D004232:Diuretics; C060942:candoxatrilat; D009320:Atrial Natriuretic Factor; D015260:Neprilysin