Preclinical pharmacological characterization of a novel inhibitor (UM8190) of prolylcarboxypeptidase (PRCP) was
investigated. We synthesized and evaluated a library of proline-based analogs as prospective recombinant PRCP (rPRCP) inhibitors and
inhibitors of PRCP-dependent prekallikrein (PK) activation on human pulmonary artery endothelial cells (HPAEC). Among the newly
synthesized compounds, UM8190 was further characterized in vivo using methods that encompassed a mouse carotid artery thrombosis
model and animal model of food consumption. (S)-N-dodecyl-1-((S)-pyrrolidine-2-carbonyl) pyrrolidine-2-carboxamide [Compound 3
(UM8190)] was selected for further evaluation from the initial assessment of its PRCP inhibitory action (Ki= 43 μM) coupled with its
ability to block PRCP-dependent PK activation on HPAEC (Ki= 34 μM). UM8190 demonstrated excellent selectivity against a panel of
carboxypeptidases and serine proteases and blocked bradykinin (BK) generation and BK-induced permeability by 100%, suggesting that
it may be useful in preventing the local production of large amounts of BK. Furthermore, UM8190 showed an anorexigenic effect when
systemically administered to fasted mice, reducing food intake in a dose- and time-dependent manner. In a mouse carotid artery
thrombosis model, it also demonstrated an antithrombotic effect. UM8190 is a selective PRCP inhibitor and it may represent a new
anorexigenic, and antithrombotic drug, that works by inhibiting PRCP–mediated mechanisms.
Keywords: Prolylcarboxypeptidase, thrombosis, factor XII, alpha-MSH, anorexigenic, obesity, Preclinical pharmacological, proline-base, analogs, endothelial cells (HPAEC).
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Published on: 06 August, 2012
Page: [4194 - 4206]