Synthesis and evaluation of acylguanidine FXa inhibitors.
A series of acylguanidine derivatives were prepared and investigated as inhibitors of Factor Xa (FXa). These compounds were made by guanidine acylation with carboxylic acids using carbonyl diimidazole (CDI) as the coupling reagent. Conditions for the rapid synthesis and purification of these compounds are described along with their ability to inhibit FXa. The best FXa inhibitor is 1 with a FXa IC(50) of 6 nM.
O'Connor
Stephen P
SP
Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08543-5400, USA. steve.oconnor@bms.com
Atwal
Karnail
K
Li
Chi
C
Liu
Eddie C-K
EC
Seiler
Steven M
SM
Shi
Mengxiao
M
Shi
Yan
Y
Stein
Philip D
PD
Wang
Ying
Y
D000925:Anticoagulants / Q000138:chemical synthesis / Q000494:pharmacology; D000990:Antithrombin III / Q000138:chemical synthesis* / Q000494:pharmacology*; D001777:Blood Coagulation; D002264:Carboxylic Acids / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D015951:Factor Xa / Q000737:chemistry*; D006146:Guanidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D006147:Guanine / Q000737:chemistry; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D015394:Molecular Structure
D000925:Anticoagulants; D002264:Carboxylic Acids; D006146:Guanidines; D007093:Imidazoles; D006147:Guanine; D000990:Antithrombin III; D015951:Factor Xa