ABSTRACT
Heteroalicyclic carboxamidines were synthesised and evaluated as inhibitors of nitric oxide synthases. (2R)-2-Pyrrolidinecarboxamidine, in particular, was shown to be a highly potent in vitro (IC(50)=0.12 µM) and selective iNOS inhibitor (>100-fold vs both eNOS and nNOS), with probable binding to the key anchoring glutamate residue and co-ordination to the haem iron.
Subject(s)
Amidines/chemical synthesis , Amidines/pharmacology , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Heme/antagonists & inhibitors , Heterocyclic Compounds/chemical synthesis , Nitric Oxide Synthase Type II/antagonists & inhibitors , Proline/analogs & derivatives , Amidines/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Humans , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Proline/chemical synthesis , Proline/chemistry , Proline/pharmacologyABSTRACT
Structure-based drug design was exploited in the synthesis of 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group with acyclic tertiary amide termini. Optimized hydrophobic contacts of one amide substituent in P4 were complemented by hydrophobicity-modulating features in the second, producing potent fXa inhibitors including examples with excellent anticoagulant properties.
