Rational design of boropeptide thrombin inhibitors: beta, beta-dialkyl-phenethylglycine P2 analogs of DuP 714 with greater selectivity over complement factor I and an improved safety profile.
The potent boropeptide thrombin inhibitor DuP 714 caused side effects in laboratory animals that appear to be related to its ability to inhibit complement factor I, thereby activating the complement cascade. Using X-ray crystal structure information, we have designed compounds that have greater selectivity for thrombin over factor I and that have reduced tendency to produce these side effects.
Fevig
J M
JM
DuPont Merck Pharmaceutical Company, Wilmington, DE 19880-0500, USA.
Buriak
J
J
Cacciola
J
J
Alexander
R S
RS
Kettner
C A
CA
Knabb
R M
RM
Pruitt
J R
JR
Weber
P C
PC
Wexler
R R
RR
D000818:Animals; D000991:Antithrombins / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D001896:Boron Compounds / Q000737:chemistry*; D017244:Complement Factor I / Q000187:drug effects*; D018360:Crystallography, X-Ray; D015195:Drug Design; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry*; D051381:Rats
D000991:Antithrombins; D001896:Boron Compounds; D009842:Oligopeptides; C066061:acetylphenylalanyl-prolyl-boroarginine; D017244:Complement Factor I