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).
Department of Medicinal Chemistry, AstraZeneca R&D Mölndal, S-431 83 Mölndal, Sweden. magnus.polla@astrazeneca.com
Magnus O
MO
Polla
Louise
L
Tottie
Carita
C
Nordén
Marcel
M
Linschoten
Djordje
D
Müsil
Susanne
S
Trumpp-Kallmeyer
Inger R
IR
Aukrust
Rune
R
Ringom
Kjetil H
KH
Holm
Siren M
SM
Neset
Marcel
M
Sandberg
John
J
Thurmond
Peng
P
Yu
Georgeta
G
Hategan
Herb
H
Anderson
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