Direct Thrombin Inhibition Reduces Lung Collagen, Accumulation, and Connective Tissue Growth Factor mRNA Levels in Bleomycin-Induced Pulmonary Fibrosis

Q2 · MEDICINE

Article

Author: Gordon Purdy ; Robin J. McAnulty ; Rachel C. Chambers ; David C.J. Howell ; Richard P. Marshall ; Geoffrey J. Laurent ; Richard Starke ; Neil R. Goldsack

Dramatic activation of the coagulation cascade has been extensively documented for pulmonary fibrosis associated with acute and chronic lung injury. In addition to its role in hemostasis, thrombin exerts profibrotic effects via activation of the major thrombin receptor, protease-activated receptor-1. In this study, we examined the effect of the direct thrombin inhibitor, UK-156406 on fibroblast responses in vitro and on bleomycin-induced pulmonary fibrosis in rats. UK-156406 significantly inhibited thrombin-induced fibroblast proliferation, procollagen production, and connective tissue growth factor (CTGF) mRNA levels when used at equimolar concentration to the protease. Thrombin levels in bronchoalveolar lavage fluid and expression of thrombin and protease-activated receptor-1 in lung tissue were increased after intratracheal instillation of bleomycin. The characteristic doubling in lung collagen in bleomycin-treated animals (38.4 +/- 2.0 mg versus 17.1 +/- 1.4 mg, P < 0.01) was preceded by significant elevations in alpha1(I) procollagen and CTGF mRNA levels (3.0 +/- 0.4-fold and 6.3 +/- 0.4-fold respectively, (P < 0.01), and total inflammatory cell number. UK-156406, administered at an anticoagulant dose, attenuated lung collagen accumulation in response to bleomycin by 35 +/- 12% (P < 0.05), inhibited alpha1(I) procollagen and CTGF mRNA levels by 50% and 35%, respectively (P < 0.05), but had no effect on inflammatory cell recruitment. This is the first report showing that direct thrombin inhibition abrogates lung collagen accumulation in bleomycin-induced pulmonary fibrosis.

01 Mar 1999·Medicinal Research ReviewsQ1 · MEDICINE

Small, noncovalent serine protease inhibitors

Q1 · MEDICINE

Review

Author: Sanderson, P E

Thrombin and factor Xa (fXa) are the only serine proteases for which small, potent, selective, noncovalent inhibitors have been developed, which are ultimately intended as drug development candidates (in this case as anticoagulants). Noncovalent inhibitors may be more selective and chemically and metabolically less reactive than covalent inhibitors. In addition, noncovalent inhibitors are more likely to have fast-binding kinetics which is particularly important in the development of thrombin inhibitors. TAME derived noncovalent thrombin inhibitors argatroban, napsagatran, and UK 156,406 have entered clinical trials as anticoagulants, the latter as an orally active agent. Serine trap deletion from substrate-like peptides led to the development of inogatran and melagatran, both of which have entered clinical trials as intravenous agents. The use of 3-aminopyridinone and pyrazinone acetamide peptidomimetic templates has resulted in the development of L-375,378 which has been chosen for clinical development as an orally active anticoagulant. Recently, compounds which do not have the conventional hydrogen bonding capabilities of peptides have begun to appear in the thrombin literature. Publications on noncovalent fXa inhibitors cover this type of peptidomimetic almost exclusively.

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Indication	Highest Phase	Country/Location	Organization	Date
Thrombosis	Phase 1	GB	Pfizer Inc.	-

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