Small, noncovalent serine protease inhibitors

Thrombin and factor Xa (fXa) are the only serine proteases for which small, potent, selective, noncovalent inhibitors have been developed, which are u ltimately intended as drug development candidates (in this case as anticoag ulants). Noncovalent inhibitors may be more selective and chemically and me tabolically less reactive than covalent inhibitors. In addition, noncovalen t inhibitors an more likely to have fast-binding kinetics which is particul arly important in the development of thrombin inhibitors. TAME derived nonc ovalent thrombin inhibitors argatroban, napsagatran, and UK 156,406 have en tered clinical trials as anticoagulants, the latter as an orally active age nt. Serine trap deletion from substrate-like peptides led to the developmen t of inogatran and melagatran, both of which have entered clinical trials a s intravenous agents. The use of 3-aminopyridinone and pyrazinone acetamide peptidomimetic templates has resulted in the development of L-375,378 whic h has been chosen for clinical development as an orally active anticoagulan t. Recently, compounds which do not have the conventional hydrogen bonding capabilities of peptides have begun to appear in the thrombin literature. P ublications on noncovalent fXa inhibitors cover this type of peptidomimetic almost exclusively. (C) 1999 John Wiley & Sons. Inc.