Received for publication February 14, 2005.
Revised August 31, 2005.
Accepted for publication August 31, 2005.

Mechanism of Vasopeptidase Inhibitor-Induced Plasma Extravasation: Comparison of Omapatrilat and the Novel NEP:ACE Inhibitor GW796406

Abstract

We describe GW796406, a vasopeptidase inhibitor (VPI) that possesses ~3-fold selectivity for NEP versus ACE in vitro assays using rat and human enzymes. In the same assays, omapatrilat, the most extensively studied VPI, displayed ~3-fold selectivity for ACE. The in vivo ACE and NEP inhibition profile and the liability of the compounds to increase plasma extravasation were compared at two (low and high) therapeutically equivalent intravenous doses in the rat. At the low doses both agents inhibited ACE activity by ~85%. Consistent with their in vitro ACE:NEP selectivity, omapatrilat produced 49% inhibition while GW796406 produced >95% inhibition of NEP. Neither compound increased plasma extravasation. When the low dose was administered to rats pretreated with the NEP inhibitor, ecadotril, to normalize NEP background to <5% of control, only omapatrilat significantly increased plasma extravasation. At the high dose, omapatrilat and GW796406 produced profound, non-selective inhibition of ACE (>90%) and NEP (>95%) and significantly increased plasma extravasation. The activity of the agents as inhibitors of DPP IV and APP was also investigated. Neither compound inhibited DPP IV. Interestingly, omapatrilat, but not GW796406, was a relatively potent inhibitor of APP (IC50= 260 nM). We investigated if APP inhibition would increased the plasma extravasation liability of GW796406. The low dose of GW796406 administered with apstatin, an APP inhibitor, did not increase plasma extravasation. This finding inferred that APP inhibition is not involved in plasma extravasation in the rat and APP inhibition does not explain the increased plasma extravasation produced by omapatrilat in NEP inhibited rats.

Key words: GW796406X, aminopeptidase P, angioedema, omapatrilat, rat, vasopeptidase-inhibitors

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