Pyrrole compounds as Granzyme B inhibitors

#Granzyme B is a pro-apoptotic serine protease found in the granules of cytotoxic lymphocytes (CTL) and natural killer (NK) cells. Granzyme B is released towards target cells, along with the pore-forming protein, perforin, resulting in its perforin-dependent internalization into the cytoplasm and subsequent induction of apoptosis (see, for e.g., Medema et al., Eur. J. Immunol. 27:3492-3498, 1997). However, during aging, inflammation and chronic disease, Granzyme B can also be expressed and secreted by other types of immune (e.g., mast cell, macrophage, neutrophil, and dendritic cells) or non-immune (keratinocyte, chondrocyte) cells and has been shown to possess extracellular matrix remodeling activity (Choy et al., Arterioscler. Thromb. Vasc. Biol. 24(12):2245-2250, 2004 and Buzza et al., J. Biol. Chem. 280:23549-23558, 2005).

#Inhibitors of Granzyme B in humans have been limited to (a) relatively weak, nonspecific inhibitors such as isocoumarins (Odake et al., (1991), Biochemistry, 30(8), 2217-2227); (b) biological inhibitors such as serpinB9 (Sun et al., (1996), J. Biol. Chem., 271(44), 27802-27809); (c) covalently coupled inhibitors such as aldehydes (Willoughby et al., (2002), Bioorg. Med. Chem. Lett., 12(16), 2197), halomethyl ketones (Kam et al., (2000), Biochim. Biophy. Acta, 1477(1-2), 307-323), and phosphonates (Mahrus and Craik, (2005), Chem. & Biol., 12, 567-77 and Kam et al., (2000)); and (d) tricyclic inhibitors (Willoughby et al., (2002)).

#Nonspecific inhibitors (such as isocoumarins) are not sufficiently potent or specific to be effective treatments for Granzyme-B-related diseases, disorders, and conditions. Likewise, the use of biological inhibitors such as serpins is limited by the ability to deliver the inhibitor to the target mammal, the cost of manufacturing the biological agents, and other, off-target activities, such as inhibition of other serine proteases such as human neutrophil elastase (Dahlen et al., (1999), Biochim. Biophys. Acta, 1451(2-3), 233-41), Caspase-1 (Annaud et al., (1999), Biochem. J., September 15; 342 Pt3, 655-65; Krieg et al., (2001), Mol. Endocrinol., 15(11), 1971-82; and Young et al., (2000), J. Exp. Med., 191(9), 1535-1544); Caspase-4 and Caspase-8 (Annaud et al., (1999)).

#FIG. 1 is a schematic illustration of a representative synthetic pathway for the preparation of representative compounds of the invention P5-P4-P3-P2-P1 starting from P1.

#FIG. 2 is a schematic illustration of another representative synthetic pathway for the preparation of representative compounds of the invention P5-P4-P3-P2-P1 starting from P5.

#FIG. 3 is a schematic illustration of a further representative synthetic pathway for the preparation of representative compounds of the invention P5-P4-P3-P2-P1 starting from a component other than P1 or P5.

#The present invention provides Granzyme B inhibitor compounds, compositions that include the compounds, and methods for using the compounds. The compounds of the invention effectively inhibit Granzyme B.

#In one aspect of the invention, the invention provides Granzyme B inhibitor compounds.

#In one embodiment, the invention provides the compounds having Formula (I):