Design and synthesis of potent, orally active, inhibitors of carboxypeptidase U (TAFIa).
A series of 3-mercapto-propionic acid derivatives that function as reversible inhibitors of carboxypeptidase U have been prepared. We present a successful design strategy using cyclic, low basicity guanidine mimetics resulting in potent, selective and bioavailable inhibitors of carboxypeptidase U (TAFIa).
Polla
Magnus O
MO
Department of Medicinal Chemistry, AstraZeneca R&D Mölndal, S-431 83 Mölndal, Sweden. magnus.polla@astrazeneca.com
Tottie
Louise
L
Nordén
Carita
C
Linschoten
Marcel
M
Müsil
Djordje
D
Trumpp-Kallmeyer
Susanne
S
Aukrust
Inger R
IR
Ringom
Rune
R
Holm
Kjetil H
KH
Neset
Siren M
SM
Sandberg
Marcel
M
Thurmond
John
J
Yu
Peng
P
Hategan
Georgeta
G
Anderson
Herb
H
D015097:3-Mercaptopropionic Acid / Q000138:chemical synthesis* / Q000494:pharmacology; D000284:Administration, Oral; D001682:Biological Availability; D025901:Carboxypeptidase B2 / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D019791:Guanidine; D006801:Humans; D020128:Inhibitory Concentration 50; D018716:Molecular Mimicry; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D015097:3-Mercaptopropionic Acid; D025901:Carboxypeptidase B2; D019791:Guanidine