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Inhibitors of adp-ribosyl transferases, cyclases, and hydrolasesRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, , Nitrogen Containing Hetero RingInhibitors of adp-ribosyl transferases, cyclases, and hydrolases description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060089318, Inhibitors of adp-ribosyl transferases, cyclases, and hydrolases. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation-in-part of U.S. patent application Ser. No. 10/158,636, filed May 30, 2003. BACKGROUND [0003] (1) Field of the Invention [0004] The present invention generally relates to inhibitors of ADP-ribosyl transferases, cyclases and hydrolases, and NAD-dependent deacetylases, including CD38. More specifically, the invention relates to improved inhibitors of those enzymes, and inhibitor pro-drugs, where the inhibitors are designed according to the mechanism of the enzymes' action. [0005] (2) Description of the Related Art REFERENCES CITED [0006] Ashamnu, G. A., Sethi, J. K., Galione, A., and Potter, B. V. L. (1997) Biochemistry, 36, 9509-9517. [0007] Bailey, V. C., Fortt, S. M., Summerhill, R. J., Galione, A., and Potter, B. V. L. (1996) FEBS Lett. 379, 227-228. [0008] Bethelier, V., Tixier, J. M., Muller-Steffner, H., Schuber, F., and Deterre, P. (1998) Biochem J. 330, 1383-1390. [0009] Clapper, D. L., Walseth, T. F., Dargie, P. J., and Lee, H. C. (1987) J. Biol. Chem. 262, 9561-9568. [0010] Cockayne et al. (1998) Blood 92, 1324-1333. [0011] Fernandez, J. E., Deaglio, S., Donati, D., Saoboda Beusan, I., and Corno, F. (1998) J. Biol. Regul. Homeostatic Agents 12, 81-91. [0012] Fox, J. J., Yung, N. C., Wempen, I., and Hoffer, M. (1961) J. Am. Chem. Soc 83, 4066-4072. [0013] Galione, A., Lee, H. C., and Busa, W. B. (1997) Science 253, 1143-1146. [0014] Handlon, A. L., Oppenheimer, N. J. (1991) J. Org. Chem. 56, 5009-5010. [0015] Hara-Yokoyama, M., Nagatsuka, Y., Katsumata, O. Irie, F., Kontani, K., Hoshino, S., Katada, T., Ono, Y., Fujita-Yoshhigaki, J., Sugiya, H., Furuyama, S., and Hirabayashi, Y. (2001) Biochemistry 40, 888-95. [0016] Howard, M., Grimaldi, J. C., Bazan, J. F., Lund, F. E., and Santos-Argumedo, L. (1993) Science 262, 1056-1059. [0017] Itoh, M., Ishihara, K., Tomzawa, H., Tanaka, H., Kobune, Y., and Ishikawa, J. (1994) Biochem. Biophys. Res. Commun. 203, 1309-1317. [0018] Jackson, D. G., and Bell, J. I. (1990) J. Immunol. 144, 2811-2815. [0019] Jiang et al. (1998) J. Biol. Chem. 273, 11017. [0020] Kaisho, T., Ishikawa, J., Oritani, K., Inazawa, J., Tomizawa, H., and Muroaka, O. (1994) Proc. Natl. Acad. Sci. USA 91, 5325-5329. [0021] Kang et al. (1998) Nucleosides Nucleotides 17, 1089. [0022] Kato, I., Takasawa, S., Akabane, A., Tanaka, O., and Abe, H. (1995) J. Biol. Chem. 270, 30045-30050. [0023] Khoo, K. M., and Chang, C. F. (2000) Arch. Biochem. Biophys. 373, 35-43. [0024] Kruppa et al. (1997) Bioorg. Med. Chem. Lett. 7, 945. [0025] Lee, H. C. (1996) Recent Prog. Horm. Res. 51, 355-388. [0026] Lee, H. C. (2001) Annu. Rev. Pharmacol. Toxicol. 41, 317-345. [0027] Lee, H. C., and Aarhus, R. (1991) Cell Regul. 2, 203-209. [0028] Lee, H. C., and Aarhus, R. (1998) Biochim. Biophys. Acta 1425, 263-271. [0029] Lee, H. C., Aarhus, R., and Levitt, D. (1994) Nature Struct. Biol. 1, 143-144. [0030] Lee et al. (1997) Tetrahedron 53, 12017. [0031] Mehta et al. (1996) FASEB J. 10, 1408-1417. [0032] Merkler et al. (1990) Biochemistry 29, 8358-8364. [0033] Mizuguchi, M., Otsuka, N., Sato, M., Ishii, Y., and Kon, S. (1995) Brain Res. 697, 235-240. [0034] Muller-Steffner, H. M., Malver, O., Hosie, L., Oppenheimer, N. J. and Schuber. F. (1992) J. Biol. Chem. 267, 9606-9611. [0035] Munshi, C., Theil, D., Mathews, I. J., Aarhus, R., Walseth, T. F, and Lee, H. C. (1999) J. Biol. Chem. 274, 30770-30777. [0036] Normark, S., Normark, B. H., and Hornet, M. (2001) Nat. Med. 11, 1182-1184. [0037] Okamoto, H. (1999) Mol. Cell. Biochem. 193, 115-118. [0038] Oppenhemer, N. J., Handlon, A. L. In The Enzymes, Sigman, D. L. Ed., Academic Press Inc: San Diego Calif., 1992, Chapter 10, vol 20, pp 453-505. [0039] Partida-Sanchez, S., Cockayne, D. A., Monard, S., Jacobson, E. L., Oppenheimer, N., Garvy, B., Kusserm K., Goodrich, S., Howard, M., Harmsen, A., Randall, T. D., and Lund, F. E. (2001) Nat. Med. 11, 1209-1216. [0040] Porter, D. J., Merrill, B. M., and Short, S. A. (1995) J. Biol. Chem. 270, 15551-15556. [0041] Reyes-Harde et al. (1999) Proc. Natl. Acad. Sci. USA 96, 4061-4066. [0042] Rusinko, N., and Lee, H. C. (1989) J. Biol. Chem. 264, 11725-11731. [0043] Sato, A., Yanamoto, S., Kajimura, N., Oda, M., Usukura, J., and Jingami, H. (1999a) Eur J Biochem 264, 439-45. [0044] Sato, A., Yamamoto, S., Ishihara, K., Hirano, T., J., and Jingami, H. (1999b) Biochem. J. 337, 491-6. [0045] Sauve, A. A. and Schramm, V. L. (2002) Biochemistry 41, 8455-8463. [0046] Sauve, A. A., Munshi, C., Lee, H. C., and Schramm, V. L. (1998) Biochemistry 37, 13239-13249. [0047] Sauve, A. A. Deng, H. T., Angeletti, R. H., and Schramm, V. L. (2000) J. Am. Chem. Soc. 122, 7855-7859. [0048] Sethi, J. K., Empson, R. M., Bailey, V. C., Potter, B. V. L., and Galione, A. (1997) J. Biol. Chem. 272, 16358-16363. [0049] Sleath, P. R., Handlon, A. L., and Oppenheimer, N. J. (1991) J. Org. Chem. 56, 3608-3613. [0050] States, D. J., Walseth, T. F., and Lee, H. C. (1992) Trends Biochem. Sci. 17, 495. [0051] Sun et al. (1999) Cell. Biol. 146, 1161-1171. [0052] Wall, K. A., Klis, M., Kornet, J., Coyle, D., Ame, J. C., Jacobson, M. K., and Slama, J. T. (1998) Biochem. J. 335, 631-636. [0053] Walseth, T. F., and Lee, H. C. (1993) Biochim. Biophys. Acta 1178, 235-242. [0054] Walseth, T. F., Aarhus, R., Kerr, J. A., and Lee, H. C. (1993) J. Biol. Chem. 268, 26686-26691. [0055] Withers, S. G. (2000) Acc. Chem. Res. 33, 11-18. [0056] Wong, L., Aarhus R., Lee H. C., and Walseth, T. F. (1999) Biochim. Biophys. Acta 1472, 555-64. [0057] Wu, Y., Kuzma, J., Marechal, E., Graeff, R., and Lee, H. C. (1997) Science 278, 2126-2130. [0058] Yamamoto-Katayama, S., Ariyoshi, M., Ishihara, K., Hirano, T., Jingami, H., and Morikawa, K. (2002) J. Mol. Biol. 316, 711-723. [0059] CD38 is a membrane anchored homodimeric ectoenzyme common to a variety of immune cells (Jackson and Bell, 1990) and other tissues (Fernandez et al., 1998) including pancreas (Kato et al., 1995) kidney (Khoo and Chang, 2000) and brain (Mizuguchi et al., 1995). CD38 is homologous to BST-1 (Kaisho et al., 1994; Itoh et al., 1994), bone stromal cell antigen, and invertebrate ADP-ribosyl cyclases (Lee and Aarhus, 1991; States et al., 1992) and catalyzes the formation of cyclic-ADP-ribose (cADPR, Lee et al., 1994) from NAD.sup.+ (Scheme 1, Rusinke and Lee, 1989). cADPR is a potent second messenger that directly activates Ca.sup.+2 release inside of cells via an IP.sub.3 independent mechanism (Lee, 2001; Lee, 1995; Clapper et al., 1987) thought to be mediated by ryanodine receptors (Lee, 2001). Recent evidence indicates that cADPR and CD38 plays a crucial role in the human immune response by activation of the cell-mediated neutrophil response to bacterial infection (Partida-Sanchez et al., 2001) and associated inflammatory physiology (Id.; Normark et al., 2001). ADP-ribosyl-cyclase and cADPR signaling has also been demonstrated in plants as mediator of the abscisic acid activated stress response (Wu et al., 1997). [0060] Not surprisingly, the ADP-ribosyl cyclases have been targets for inhibitor design (Sleath et al., 1991; Muller-Steffner et al., 1992; Bethelier et al., 1998; Wall et al., 1998; Sauve et al., 2000). Also, analogs of cADPR with antagonistic (Sato et al., 1999a; Sato et al., 1999b; Hara-Yokoyama et al., 2001; Walseth and Lee, 1993), or agonistic (Sethi et al., 1997; Walseth et al., 1993; Ashamu et al., 1997; Galione et al., 1997; Wong et al., 1999; Lee and Aarhus, 1998; Baily et al., 1996) properties have been reported. Most of the inhibitors and cADPR analogs are phosphorylated compounds (Lee, 2001), and have practical limitations affecting their use in whole cell or whole tissue investigations, because of the difficulty of passing charges across cell membranes (Id.). Although altered inhibitor structure to nucleosides could potentially make compounds more cell permeant, no reports of nucleoside-based CD38 or ADP-ribosyl-cyclase inhibitors have appeared. [0061] In prior work, the mononucleotide ara-F-NMN.sup.+ was shown to be a potent inhibitor of CD38 with a K.sub.i value of 61 nM (Sauve et al., 2000). This K.sub.i is similar to the dinucleotide inhibitor ara-F-NAD.sup.+ (Sleath et al., 1991), where a K.sub.i value of 169 nM was reported (Muller-Steffner et al., 1992). [0062] In other work, mechanism-based inhibitors of ADP-ribosyl transferases, cyclases and hydrolases, and NAD-dependent deacetylases were found to have several advantages to the above nucleotide-based inhibitors (U.S. patent application Ser. No. 10/038,760, incorporated by reference in its entirety). Those inhibitors react rapidly to form a covalent intermediate that cannot cyclize and that are relatively stable to hydrolysis, thereby trapping the enzyme in a catalytically-inactive form. Further development of these mechanism-based inhibitors to provide highly stable, potent inhibitors of ADP-ribosyl transferases, cyclases and hydrolases, and NAD-dependent deacetylases is desirable. SUMMARY OF THE INVENTION [0063] Accordingly, the inventors have discovered that providing an electron-contributing moiety to the leaving group of the mechanism-based inhibitors described in U.S. patent application Ser. No. 10/038,760 (the '760 application) greatly stabilizes the compounds to hydrolysis. The resulting improved inhibitors provide greater potential for therapeutic benefits, and provides improved reagents for studying ADP-ribosyl transferases, cyclases and hydrolases, and NAD-dependent deacetylases, including CD38. Pro-drug compounds of the inhibitors have also been developed. [0064] Thus, in some embodiments, the present invention is directed to compounds represented by the formula: where A is a nitrogen-, oxygen-, or sulfur-linked aryl, alkyl, cyclic, or heterocyclic group. In these embodiments, the group A is further substituted with an electron contributing moiety. Additionally, B is hydrogen, or a halogen, amino, or thiol group; C is hydrogen, or a halogen, amino, or thiol group; and D is a primary alcohol, a hydrogen, or an oxygen, nitrogen, carbon, or sulfur linked to phosphate, a phosphoryl group, a pyrophosphoryl group, or adenosine monophosphate through a phosphodiester or carbon-, nitrogen-, or sulfur-substituted phosphodiester bridge, or to adenosine diphosphate through a phosphodiester or carbon-, nitrogen-, or sulfur-substituted pyrophosphodiester bridge. The compounds are preferably inhibitors of ADP-ribosyl transferase, ADP-ribosyl cyclase, ADP-ribosyl hydrolase, and/or NAD-dependent deacetylase enzymes. [0065] The invention is also directed to pro-drug compounds represented by the formula: where A is a nitrogen-, oxygen-, or sulfur-linked aryl, alkyl, cyclic, or heterocyclic group; B is hydrogen, or a halogen, amino, or thiol group; C is hydrogen, or a halogen, amino, or thiol group; D is the ester --OOCR where R is an alkyl or an aryl, a primary alcohol, a hydrogen, or an oxygen, nitrogen, carbon, or sulfur linked to phosphate, a phosphoryl group, a pyrophosphoryl group, or adenosine monophosphate through a phosphodiester or carbon-, nitrogen-, or sulfur-substituted phosphodiester bridge, or to adenosine diphosphate through a phosphodiester or carbon-, nitrogen-, or sulfur-substituted pyrophosphodiester bridge; and E is OH or the ester --OOCR where R is an alkyl or an aryl. In these embodiments, at least one of D or E is the ester --OOCR where R is an alkyl or an aryl. [0066] Pharmaceutical compositions comprising the above compounds in a pharmaceutically acceptable carrier are also encompassed by the invention. [0067] In other embodiments, the invention is directed to methods for inhibiting an ADP-ribosyl transferase, ADP-ribosyl cyclase, ADP-ribosyl hydrolase or an NAD-dependent deacetylase enzyme. The methods comprise contacting the enzyme with an amount of any of the above compounds effective to inhibit the enzyme. [0068] Additionally, the invention is directed to methods for treating a disease or condition associated with an ADP-ribosyl transferase, ADP-ribosyl cyclase, ADP-ribosyl hydrolase, or NAD-dependent deacetylase enzyme in a subject in need of treatment thereof. These methods comprise administering to the subject any of the above-described inhibitor or pro-drug compounds in an amount effective to treat the disease or condition. BRIEF DESCRIPTION OF THE DRAWINGS [0069] FIG. 1 provides the structure of inhibitors 1-3. [0070] FIG. 2 provides graphs illustrating data measuring time courses of inhibition of CD38 by different concentrations of 1 as assayed by conversion of NGD.sup.+ to cGDPR (100 .mu.M NGD.sup.+). Panel A shows the initial rates of reaction of curves from Panel B were fit to the equation for competitive inhibition to determine K.sub.i in Table 2. Panel B shows the extended time courses of two-phase inhibition of CD38 by different concentrations of 1 as assayed by conversion of NGD.sup.+ to cGDPR. Inhibitor concentrations are shown. The solid lines represent the best fit to the slow-onset equation given in the text. The rate constant (k.sub.1) for the slow phase derived from these curves is 4.2.times.10.sup.-3 s.sup.-1. [0071] FIG. 3 provides a graph illustrating data measuring time course of two-phase inhibition of CD38 by different concentrations of 1 as assayed by conversion of NGD.sup.+ to cGDPR (40 .mu.M NGD.sup.+). Inhibitor concentrations are shown on the right of curves. The solid lines represent the best fit to the slow-onset equation given in the text. The rate constant (k.sub.on) for the slow phase derived from these curves is 8.3.times.10.sup.-3 s.sup.-1. The initial rates from these curves were used to determine K.sub.i (Table 2). [0072] FIG. 4 provides a graph of data from a recovery experiment to measure rate of recovery of CD38 from inhibition by 1 in the presence of excess NGD.sup.+. The top curve is a control, of uninhibited enzyme. The bottom curve shows the recovery process as increasing free CD38 generates increasing rates of cGDPR formation. The solid curve represents the best fit to the recovery equation described in the text. The recovery rate determined was 2.times.10.sup.-5 s.sup.-1. Continue reading about Inhibitors of adp-ribosyl transferases, cyclases, and hydrolases... 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