Influence of a novel inhibitor (UM8190) of prolylcarboxypeptidase (PRCP) on appetite and thrombosis.
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 (K(i)= 43 μM) coupled with its ability to block PRCP-dependent PK activation on HPAEC (K(i)= 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.
School of Pharmacy, Department of Pharmacology, University of Mississippi, University, MS 38677-1848, USA.
F M
FM
Rabey
R S V S
RS
Gadepalli
S
S
Diano
Q
Q
Cheng
T
T
Tabrizian
D
D
Gailani
J M
JM
Rimoldi
Z
Z
Shariat-Madar
D000818:Animals; D001066:Appetite / Q000187:drug effects*; D001067:Appetite Depressants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001920:Bradykinin / Q000378:metabolism; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D011288:Prekallikrein / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D013927:Thrombosis / Q000188:drug therapy / Q000473:pathology
D001067:Appetite Depressants; D005343:Fibrinolytic Agents; C578525:N-dodecyl-1-(pyrrolidine-2-carbonyl)pyrrolidine-2-carboxamide; D011480:Protease Inhibitors; D009569:Nitric Oxide; D011288:Prekallikrein; D011392:Proline; D002268:Carboxypeptidases; C022448:lysosomal Pro-X carboxypeptidase; D001920:Bradykinin