Rational approaches to discovery of orally active and brain-penetrable quinazolinone inhibitors of poly(ADP-ribose)polymerase

Journal of Medicinal Chemistry

Volumn 47, Issue 17, 2004, Pages 4151-4154

  Hattori, Kouji ^a   Kido, Yoshiyuki ^a   Yamamoto, Hirofumi ^a   Ishida, Junya ^a   Kamijo, Kazunori ^a   Murano, Kenji ^a   Ohkubo, Mitsuru ^a   Kinoshita, Takayoshi ^a   Iwashita, Akinori ^a   Mihara, Kayoko ^a   Yamazaki, Syunji ^a   Matsuoka, Nobuya ^a   Teramura, Yoshinori ^a   Miyake, Hiroshi ^a  

^a ASTELLAS PHARMA INC   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE DERIVATIVE; ADENOSINE RIBOSE; NICOTINAMIDE ADENINE DINUCLEOTIDE; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE INHIBITOR; NICOTINAMIDE RIBOSIDE; QUINAZOLINE DERIVATIVE; QUINAZOLINEDIONE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; COMBINATORIAL CHEMISTRY; CONTROLLED STUDY; DRUG ACTIVITY; DRUG BINDING SITE; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG BRAIN LEVEL; DRUG PENETRATION; DRUG POTENCY; DRUG RESEARCH; DRUG SCREENING; DRUG STRUCTURE; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; BIOLOGICAL AVAILABILITY; BLOOD-BRAIN BARRIER; BRAIN; CATALYTIC DOMAIN; COMBINATORIAL CHEMISTRY TECHNIQUES; DOGS; HUMANS; MICE; MICE, INBRED C57BL; MICROSOMES, LIVER; MODELS, MOLECULAR; PARKINSONIAN DISORDERS; POLY(ADP-RIBOSE) POLYMERASES; QUINAZOLINES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 3843071128     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0499256     Document Type: Article

References (35)

1. Recent reviews on PARP: Nguewa, P. A.; Fuertes, M. A.; Alonso, C.; Petéz, J. M. Pharmacological modulation of poly(ADP-ribose)polymerase mediated cell death: exploitation in cancer chemotherapy. Mol. Pharmacol. 2003, 64, 1007-1014. Chiarugi, I. Poly(ADP-ribose)polymerase: killer or conspirator? The suicide hypothesis' revisited. TIPS 2002, 23, 122-129. Szabó, C.; Virag, L. The therapeutic potential of poly(ADP-ribose)polymerase inhibitors. Pharmacol. Rev. 2002, 54, 375-429. From DNA Damage and Stress Signaling to Cell Death: Poly ADP-Ribosylation Reactions; de Murcia, G., Shall, S., Eds; Oxford University Press: Oxford, 2000. Cell Death: The Role of PARP; Szabó, C., Ed.; CRC Press: Boca Raton, FL, 2000 and references therein.
2. Recent reviews on PARP: Nguewa, P. A.; Fuertes, M. A.; Alonso, C.; Petéz, J. M. Pharmacological modulation of poly(ADP-ribose)polymerase mediated cell death: exploitation in cancer chemotherapy. Mol. Pharmacol. 2003, 64, 1007-1014. Chiarugi, I. Poly(ADP-ribose)polymerase: killer or conspirator? The suicide hypothesis' revisited. TIPS 2002, 23, 122-129. Szabó, C.; Virag, L. The therapeutic potential of poly(ADP-ribose)polymerase inhibitors. Pharmacol. Rev. 2002, 54, 375-429. From DNA Damage and Stress Signaling to Cell Death: Poly ADP-Ribosylation Reactions; de Murcia, G., Shall, S., Eds; Oxford University Press: Oxford, 2000. Cell Death: The Role of PARP; Szabó, C., Ed.; CRC Press: Boca Raton, FL, 2000 and references therein.
3. Recent reviews on PARP: Nguewa, P. A.; Fuertes, M. A.; Alonso, C.; Petéz, J. M. Pharmacological modulation of poly(ADP-ribose)polymerase mediated cell death: exploitation in cancer chemotherapy. Mol. Pharmacol. 2003, 64, 1007-1014. Chiarugi, I. Poly(ADP-ribose)polymerase: killer or conspirator? The suicide hypothesis' revisited. TIPS 2002, 23, 122-129. Szabó, C.; Virag, L. The therapeutic potential of poly(ADP-ribose)polymerase inhibitors. Pharmacol. Rev. 2002, 54, 375-429. From DNA Damage and Stress Signaling to Cell Death: Poly ADP-Ribosylation Reactions; de Murcia, G., Shall, S., Eds; Oxford University Press: Oxford, 2000. Cell Death: The Role of PARP; Szabó, C., Ed.; CRC Press: Boca Raton, FL, 2000 and references therein.
4. Recent reviews on PARP: Nguewa, P. A.; Fuertes, M. A.; Alonso, C.; Petéz, J. M. Pharmacological modulation of poly(ADP-ribose)polymerase mediated cell death: exploitation in cancer chemotherapy. Mol. Pharmacol. 2003, 64, 1007-1014. Chiarugi, I. Poly(ADP-ribose)polymerase: killer or conspirator? The suicide hypothesis' revisited. TIPS 2002, 23, 122-129. Szabó, C.; Virag, L. The therapeutic potential of poly(ADP-ribose)polymerase inhibitors. Pharmacol. Rev. 2002, 54, 375-429. From DNA Damage and Stress Signaling to Cell Death: Poly ADP-Ribosylation Reactions; de Murcia, G., Shall, S., Eds; Oxford University Press: Oxford, 2000. Cell Death: The Role of PARP; Szabó, C., Ed.; CRC Press: Boca Raton, FL, 2000 and references therein.
5. Recent reviews on PARP: Nguewa, P. A.; Fuertes, M. A.; Alonso, C.; Petéz, J. M. Pharmacological modulation of poly(ADP-ribose)polymerase mediated cell death: exploitation in cancer chemotherapy. Mol. Pharmacol. 2003, 64, 1007-1014. Chiarugi, I. Poly(ADP-ribose)polymerase: killer or conspirator? The suicide hypothesis' revisited. TIPS 2002, 23, 122-129. Szabó, C.; Virag, L. The therapeutic potential of poly(ADP-ribose)polymerase inhibitors. Pharmacol. Rev. 2002, 54, 375-429. From DNA Damage and Stress Signaling to Cell Death: Poly ADP-Ribosylation Reactions; de Murcia, G., Shall, S., Eds; Oxford University Press: Oxford, 2000. Cell Death: The Role of PARP; Szabó, C., Ed.; CRC Press: Boca Raton, FL, 2000 and references therein.
6. LaPlaca, M. C.; Zhang, J.; Raghupathi, R.; Li, J. H.; Smith, F.; Bareyre, F. M.; Snyder, S. H.; Graham, D. I.; McIntosh, T. K. Pharmacologic inhibition of poly(ADP-ribose)polymerase is neuroprotective following traumatic brain injury in rats. J. Neurotrauma 2001, 18 (4), 369-376. Abdelkarim, G. E.; Harms, C.; Katchanov, J.; Dirnagl, U.; Szabó, C.; Endres, M. Protective effects of PJ34, a novel, potent inhibitor of poly(ADP-ribose)polymerase (PARP) in in vitro and in vivo models of stroke. Int. J. Mol. Med. 2001, 7 (3), 255-260. Takahashi, K.; Pieper, A. A.; Croul, S. E.; Zhang, J.; Snyder, S. H.; Greenberg, J. H. Posttreatment with an inhibitor of poly(ADP-ribose)polymerase attenuates cerebral damage in focal ischemia. Brain Res. 1999, 829 (1-2), 46-54. Cosi, C.; Colpaert, F.; Koek, W.; Degryse, A.; Marien, M. Poly(ADP-ribose)polymerase inhibitors protect against MPTP-induced depletions of striatal dopamine and cortical noradrenaline in C57BL/6 mice. Brain Res. 1996, 729, 264-269.
7. LaPlaca, M. C.; Zhang, J.; Raghupathi, R.; Li, J. H.; Smith, F.; Bareyre, F. M.; Snyder, S. H.; Graham, D. I.; McIntosh, T. K. Pharmacologic inhibition of poly(ADP-ribose)polymerase is neuroprotective following traumatic brain injury in rats. J. Neurotrauma 2001, 18 (4), 369-376. Abdelkarim, G. E.; Harms, C.; Katchanov, J.; Dirnagl, U.; Szabó, C.; Endres, M. Protective effects of PJ34, a novel, potent inhibitor of poly(ADP-ribose)polymerase (PARP) in in vitro and in vivo models of stroke. Int. J. Mol. Med. 2001, 7 (3), 255-260. Takahashi, K.; Pieper, A. A.; Croul, S. E.; Zhang, J.; Snyder, S. H.; Greenberg, J. H. Posttreatment with an inhibitor of poly(ADP-ribose)polymerase attenuates cerebral damage in focal ischemia. Brain Res. 1999, 829 (1-2), 46-54. Cosi, C.; Colpaert, F.; Koek, W.; Degryse, A.; Marien, M. Poly(ADP-ribose)polymerase inhibitors protect against MPTP-induced depletions of striatal dopamine and cortical noradrenaline in C57BL/6 mice. Brain Res. 1996, 729, 264-269.
8. LaPlaca, M. C.; Zhang, J.; Raghupathi, R.; Li, J. H.; Smith, F.; Bareyre, F. M.; Snyder, S. H.; Graham, D. I.; McIntosh, T. K. Pharmacologic inhibition of poly(ADP-ribose)polymerase is neuroprotective following traumatic brain injury in rats. J. Neurotrauma 2001, 18 (4), 369-376. Abdelkarim, G. E.; Harms, C.; Katchanov, J.; Dirnagl, U.; Szabó, C.; Endres, M. Protective effects of PJ34, a novel, potent inhibitor of poly(ADP-ribose)polymerase (PARP) in in vitro and in vivo models of stroke. Int. J. Mol. Med. 2001, 7 (3), 255-260. Takahashi, K.; Pieper, A. A.; Croul, S. E.; Zhang, J.; Snyder, S. H.; Greenberg, J. H. Posttreatment with an inhibitor of poly(ADP-ribose)polymerase attenuates cerebral damage in focal ischemia. Brain Res. 1999, 829 (1-2), 46-54. Cosi, C.; Colpaert, F.; Koek, W.; Degryse, A.; Marien, M. Poly(ADP-ribose)polymerase inhibitors protect against MPTP-induced depletions of striatal dopamine and cortical noradrenaline in C57BL/6 mice. Brain Res. 1996, 729, 264-269.
9. LaPlaca, M. C.; Zhang, J.; Raghupathi, R.; Li, J. H.; Smith, F.; Bareyre, F. M.; Snyder, S. H.; Graham, D. I.; McIntosh, T. K. Pharmacologic inhibition of poly(ADP-ribose)polymerase is neuroprotective following traumatic brain injury in rats. J. Neurotrauma 2001, 18 (4), 369-376. Abdelkarim, G. E.; Harms, C.; Katchanov, J.; Dirnagl, U.; Szabó, C.; Endres, M. Protective effects of PJ34, a novel, potent inhibitor of poly(ADP-ribose)polymerase (PARP) in in vitro and in vivo models of stroke. Int. J. Mol. Med. 2001, 7 (3), 255-260. Takahashi, K.; Pieper, A. A.; Croul, S. E.; Zhang, J.; Snyder, S. H.; Greenberg, J. H. Posttreatment with an inhibitor of poly(ADP-ribose)polymerase attenuates cerebral damage in focal ischemia. Brain Res. 1999, 829 (1-2), 46-54. Cosi, C.; Colpaert, F.; Koek, W.; Degryse, A.; Marien, M. Poly(ADP-ribose)polymerase inhibitors protect against MPTP-induced depletions of striatal dopamine and cortical noradrenaline in C57BL/6 mice. Brain Res. 1996, 729, 264-269.
10. Recent studies have demonstrated that dopaminergic neurons lacking the gene coding PARP are spared from the neurotoxic effects of MPTP: Mandir, A. S.; Przedborski, S.; Jackson-Lewis, V.; Wang, Z.; Simbulan-Rosenthal, C. M.; Smulson, M. E.; Hoffman, B. E.; Guastella, D. B.; Dawson, V. L.; Dawson, T. M. Poly(ADP-ribose)polymerase activation mediates 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine(MPTP)-induced parkinsonism. Proc. Natl. Acad. Aci. U.S.A. 1999, 96, 5774-5779.
11. Recent reviews: Southan, G. J.; Szabó, C. Poly(ADP-ribose) polymerase inhibitors. Curr. Med. Chem. 2003, 10, 321-340. Cosi, C. New inhibitors of poly(ADP-ribose)polymerase and their potential therapeutic targets. Expert Opin. Ther. Pat. 2002, 12, 1047-1071.
12. Recent reviews: Southan, G. J.; Szabó, C. Poly(ADP-ribose) polymerase inhibitors. Curr. Med. Chem. 2003, 10, 321-340. Cosi, C. New inhibitors of poly(ADP-ribose)polymerase and their potential therapeutic targets. Expert Opin. Ther. Pat. 2002, 12, 1047-1071.
13. Some quinazolinone-based PARP inhibitors have been identified. (a) Griffin, R. J.; Srinivasan, S.; Bowman, K.; Calvert, A. H.; Curtin, N. J.; Newell, D. R.; Pemberton, L. C.; Golding, B. T. Resistance-modifying agents. 5. Synthesis and biological properties of quinazolinone inhibitors of the DNA repair enzyme poly(ADP-ribose)polymerase (PARP). J. Med. Chem. 1998, 41, 5247-5256.
14. (b) Banasik, M.; Komura, H.; Shimoyama, M.; Ueda, K. Specific inhibitors of poly(ADP-ribose)synthetase and mono(ADP-ribosyl)transferase. J. Biol. Chem. 1992, 267, 1569-1575.
15. The human active site of PARP-1 was completely conserved with the active site of chicken of PARP-17 except 763-amino acid (human, Glu763; chicken, Gln763).
16. + binding to poly(ADP-ribose)polymerase as derived from crystal structures and homology modeling. Biochemistry 1998, 37, 3893-3900. Ruf, A.; Murcia, J. M.; Murcia, G. M.; Schulz, G. E. Structure of the catalytic fragment of poly(ADP-ribose) polymerase from chicken. Proc. Natl. Acad. Aci. U.S.A. 1996, 93, 7481-7485.
17. + binding to poly(ADP-ribose)polymerase as derived from crystal structures and homology modeling. Biochemistry 1998, 37, 3893-3900. Ruf, A.; Murcia, J. M.; Murcia, G. M.; Schulz, G. E. Structure of the catalytic fragment of poly(ADP-ribose) polymerase from chicken. Proc. Natl. Acad. Aci. U.S.A. 1996, 93, 7481-7485.
18. Skalitzky, D. J.; Marakovits, J. T.; Maegley, K. A.; Ekker, A.; Yu, X.-H.; Hostomsky, Z.; Webber, S. E.; Eastman, B. W.; Almassy, R.; Li, J. Tricyclic benzimidazoles as potent poly(ADP-ribose)polymerase-1 inhibitors. J. Med. Chem. 2003, 46, 210-213. Ferraris, D.; Ficco, R. P.; Dain, D.; Ginski, M.; Lautar, S.; Lee-Wisdom, K.; Liang, S.; Lin, Q.; Lu, M. X.-C.; Morgan, L.; Thomas, B.; Williams, L. R.; Zhang, J.; Zhou, Y.; Kalish, V. J. Design and synthesis of poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors. Part 4: biological evaluation of imidazobenzodiazepines as potent PARP-1 inhibitors for treatment of ischemic injuries. Bioorg. Med. Chem. 2003, 11, 3695-3707. Canan Koch, S. S.; Thoresen, L. H.; Tikhe, J. G.; Maegley, K. A.; Almassy, R. J.; Li, J.; Yu, X.-H.; Zook, S. E.; Kumpf, R. A.; Zhang, C.; Boritzki, T. J.; Mansour, R. N.; Zhang, K. E.; Ekker, A.; Calabrese, C. R.; Curtin, N. J.; Kyle, S.; Thomas, H. D.; Wang, L.-Z.; Calvert, A. H.; Golding, B. T.; Griffin, R. J.; Newell, D. R.; Webber, S.; Hostomsky, Z. Novel tricyclic poly(ADP-ribose) polymerase-1 inhibitors with potent anticancer chemopotentiating activity: design, synthesis, and X-ray cocrystal structure. J. Med. Chem. 2002, 45, 4961-4974. Costantino, G.; Macchiarulo, A.; Camaioni, E.; Pellicciari, R. Modeling of poly(ADP-ribose)polymerase (PARP) inhibitors. Docking of ligands and quantitative structure-activity relationship analysis. J. Med. Chem. 2001, 44, 3786-3794. White, A. W.; Almassy, R.; Calvert, A. H.; Curtin, N. J.; Griffin, R. J.; Hostomsky, Z.; Maegley, K.; Newell, D. R.; Srinivasan, S.; Golding, B. T. Resistance-modifying agents. 9. Synthesis and biological properties of benzimidazole inhibitors of the DNA repair enzyme poly(ADP-ribose)polymerase. J. Med. Chem. 2000, 43, 4084-4097.
19. Skalitzky, D. J.; Marakovits, J. T.; Maegley, K. A.; Ekker, A.; Yu, X.-H.; Hostomsky, Z.; Webber, S. E.; Eastman, B. W.; Almassy, R.; Li, J. Tricyclic benzimidazoles as potent poly(ADP-ribose)polymerase-1 inhibitors. J. Med. Chem. 2003, 46, 210-213. Ferraris, D.; Ficco, R. P.; Dain, D.; Ginski, M.; Lautar, S.; Lee-Wisdom, K.; Liang, S.; Lin, Q.; Lu, M. X.-C.; Morgan, L.; Thomas, B.; Williams, L. R.; Zhang, J.; Zhou, Y.; Kalish, V. J. Design and synthesis of poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors. Part 4: biological evaluation of imidazobenzodiazepines as potent PARP-1 inhibitors for treatment of ischemic injuries. Bioorg. Med. Chem. 2003, 11, 3695-3707. Canan Koch, S. S.; Thoresen, L. H.; Tikhe, J. G.; Maegley, K. A.; Almassy, R. J.; Li, J.; Yu, X.-H.; Zook, S. E.; Kumpf, R. A.; Zhang, C.; Boritzki, T. J.; Mansour, R. N.; Zhang, K. E.; Ekker, A.; Calabrese, C. R.; Curtin, N. J.; Kyle, S.; Thomas, H. D.; Wang, L.-Z.; Calvert, A. H.; Golding, B. T.; Griffin, R. J.; Newell, D. R.; Webber, S.; Hostomsky, Z. Novel tricyclic poly(ADP-ribose) polymerase-1 inhibitors with potent anticancer chemopotentiating activity: design, synthesis, and X-ray cocrystal structure. J. Med. Chem. 2002, 45, 4961-4974. Costantino, G.; Macchiarulo, A.; Camaioni, E.; Pellicciari, R. Modeling of poly(ADP-ribose)polymerase (PARP) inhibitors. Docking of ligands and quantitative structure-activity relationship analysis. J. Med. Chem. 2001, 44, 3786-3794. White, A. W.; Almassy, R.; Calvert, A. H.; Curtin, N. J.; Griffin, R. J.; Hostomsky, Z.; Maegley, K.; Newell, D. R.; Srinivasan, S.; Golding, B. T. Resistance-modifying agents. 9. Synthesis and biological properties of benzimidazole inhibitors of the DNA repair enzyme poly(ADP-ribose)polymerase. J. Med. Chem. 2000, 43, 4084-4097.
20. Skalitzky, D. J.; Marakovits, J. T.; Maegley, K. A.; Ekker, A.; Yu, X.-H.; Hostomsky, Z.; Webber, S. E.; Eastman, B. W.; Almassy, R.; Li, J. Tricyclic benzimidazoles as potent poly(ADP-ribose)polymerase-1 inhibitors. J. Med. Chem. 2003, 46, 210-213. Ferraris, D.; Ficco, R. P.; Dain, D.; Ginski, M.; Lautar, S.; Lee-Wisdom, K.; Liang, S.; Lin, Q.; Lu, M. X.-C.; Morgan, L.; Thomas, B.; Williams, L. R.; Zhang, J.; Zhou, Y.; Kalish, V. J. Design and synthesis of poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors. Part 4: biological evaluation of imidazobenzodiazepines as potent PARP-1 inhibitors for treatment of ischemic injuries. Bioorg. Med. Chem. 2003, 11, 3695-3707. Canan Koch, S. S.; Thoresen, L. H.; Tikhe, J. G.; Maegley, K. A.; Almassy, R. J.; Li, J.; Yu, X.-H.; Zook, S. E.; Kumpf, R. A.; Zhang, C.; Boritzki, T. J.; Mansour, R. N.; Zhang, K. E.; Ekker, A.; Calabrese, C. R.; Curtin, N. J.; Kyle, S.; Thomas, H. D.; Wang, L.-Z.; Calvert, A. H.; Golding, B. T.; Griffin, R. J.; Newell, D. R.; Webber, S.; Hostomsky, Z. Novel tricyclic poly(ADP-ribose) polymerase-1 inhibitors with potent anticancer chemopotentiating activity: design, synthesis, and X-ray cocrystal structure. J. Med. Chem. 2002, 45, 4961-4974. Costantino, G.; Macchiarulo, A.; Camaioni, E.; Pellicciari, R. Modeling of poly(ADP-ribose)polymerase (PARP) inhibitors. Docking of ligands and quantitative structure-activity relationship analysis. J. Med. Chem. 2001, 44, 3786-3794. White, A. W.; Almassy, R.; Calvert, A. H.; Curtin, N. J.; Griffin, R. J.; Hostomsky, Z.; Maegley, K.; Newell, D. R.; Srinivasan, S.; Golding, B. T. Resistance-modifying agents. 9. Synthesis and biological properties of benzimidazole inhibitors of the DNA repair enzyme poly(ADP-ribose)polymerase. J. Med. Chem. 2000, 43, 4084-4097.
21. Skalitzky, D. J.; Marakovits, J. T.; Maegley, K. A.; Ekker, A.; Yu, X.-H.; Hostomsky, Z.; Webber, S. E.; Eastman, B. W.; Almassy, R.; Li, J. Tricyclic benzimidazoles as potent poly(ADP-ribose)polymerase-1 inhibitors. J. Med. Chem. 2003, 46, 210-213. Ferraris, D.; Ficco, R. P.; Dain, D.; Ginski, M.; Lautar, S.; Lee-Wisdom, K.; Liang, S.; Lin, Q.; Lu, M. X.-C.; Morgan, L.; Thomas, B.; Williams, L. R.; Zhang, J.; Zhou, Y.; Kalish, V. J. Design and synthesis of poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors. Part 4: biological evaluation of imidazobenzodiazepines as potent PARP-1 inhibitors for treatment of ischemic injuries. Bioorg. Med. Chem. 2003, 11, 3695-3707. Canan Koch, S. S.; Thoresen, L. H.; Tikhe, J. G.; Maegley, K. A.; Almassy, R. J.; Li, J.; Yu, X.-H.; Zook, S. E.; Kumpf, R. A.; Zhang, C.; Boritzki, T. J.; Mansour, R. N.; Zhang, K. E.; Ekker, A.; Calabrese, C. R.; Curtin, N. J.; Kyle, S.; Thomas, H. D.; Wang, L.-Z.; Calvert, A. H.; Golding, B. T.; Griffin, R. J.; Newell, D. R.; Webber, S.; Hostomsky, Z. Novel tricyclic poly(ADP-ribose) polymerase-1 inhibitors with potent anticancer chemopotentiating activity: design, synthesis, and X-ray cocrystal structure. J. Med. Chem. 2002, 45, 4961-4974. Costantino, G.; Macchiarulo, A.; Camaioni, E.; Pellicciari, R. Modeling of poly(ADP-ribose)polymerase (PARP) inhibitors. Docking of ligands and quantitative structure-activity relationship analysis. J. Med. Chem. 2001, 44, 3786-3794. White, A. W.; Almassy, R.; Calvert, A. H.; Curtin, N. J.; Griffin, R. J.; Hostomsky, Z.; Maegley, K.; Newell, D. R.; Srinivasan, S.; Golding, B. T. Resistance-modifying agents. 9. Synthesis and biological properties of benzimidazole inhibitors of the DNA repair enzyme poly(ADP-ribose)polymerase. J. Med. Chem. 2000, 43, 4084-4097.
22. Skalitzky, D. J.; Marakovits, J. T.; Maegley, K. A.; Ekker, A.; Yu, X.-H.; Hostomsky, Z.; Webber, S. E.; Eastman, B. W.; Almassy, R.; Li, J. Tricyclic benzimidazoles as potent poly(ADP-ribose)polymerase-1 inhibitors. J. Med. Chem. 2003, 46, 210-213. Ferraris, D.; Ficco, R. P.; Dain, D.; Ginski, M.; Lautar, S.; Lee-Wisdom, K.; Liang, S.; Lin, Q.; Lu, M. X.-C.; Morgan, L.; Thomas, B.; Williams, L. R.; Zhang, J.; Zhou, Y.; Kalish, V. J. Design and synthesis of poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors. Part 4: biological evaluation of imidazobenzodiazepines as potent PARP-1 inhibitors for treatment of ischemic injuries. Bioorg. Med. Chem. 2003, 11, 3695-3707. Canan Koch, S. S.; Thoresen, L. H.; Tikhe, J. G.; Maegley, K. A.; Almassy, R. J.; Li, J.; Yu, X.-H.; Zook, S. E.; Kumpf, R. A.; Zhang, C.; Boritzki, T. J.; Mansour, R. N.; Zhang, K. E.; Ekker, A.; Calabrese, C. R.; Curtin, N. J.; Kyle, S.; Thomas, H. D.; Wang, L.-Z.; Calvert, A. H.; Golding, B. T.; Griffin, R. J.; Newell, D. R.; Webber, S.; Hostomsky, Z. Novel tricyclic poly(ADP-ribose) polymerase-1 inhibitors with potent anticancer chemopotentiating activity: design, synthesis, and X-ray cocrystal structure. J. Med. Chem. 2002, 45, 4961-4974. Costantino, G.; Macchiarulo, A.; Camaioni, E.; Pellicciari, R. Modeling of poly(ADP-ribose)polymerase (PARP) inhibitors. Docking of ligands and quantitative structure-activity relationship analysis. J. Med. Chem. 2001, 44, 3786-3794. White, A. W.; Almassy, R.; Calvert, A. H.; Curtin, N. J.; Griffin, R. J.; Hostomsky, Z.; Maegley, K.; Newell, D. R.; Srinivasan, S.; Golding, B. T. Resistance-modifying agents. 9. Synthesis and biological properties of benzimidazole inhibitors of the DNA repair enzyme poly(ADP-ribose)polymerase. J. Med. Chem. 2000, 43, 4084-4097.
23. Recently, Szabó and co-workers have published new inhibitors linked to adenosine itself: Jagtap, P. G.; Southan, G. J.; Baloglu, E.; Ram, S.; Mabley, J. G.; Marton, A.; Salzman, A.; Szabo, C. The discovery and synthesis of novel adenosine substituted 2,3-dihydro-1H-isoindol-1-ones: potent inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1). Bioorg. Med. Chem. Lett. 2004, 14, 81-85.
24. X-ray data and the method are in the Supporting Information.
25. We have also succeeded in X-ray crystallography of the catalytic domain of human PARP-1 complexes with quinazoline derivatives. The crystal structure indicates binding to the NI site and AD subsites in a similar binding mode, as expected from modeling. The induced fitting of the inhibitors enlarges the AD site and breaks the bottom of the active site wall: Kinoshita, T.; Nakanishi, I.; Warizuka, M.; Iwashita, Y.; Kido, Y.; Hattori, K.; Fujii, T. Inhibitor-induced structural change of the active site of human poly(ADP-ribose)polymerase. FEBS Lett. 2004, 556, 43-46.
26. 3 and 5 were not obtained by this method. Their resynthesis was performed using liquid synthesis and a similar method instead of using resin.
27. Purity is >95% after purification, and yield is not optimized. A typical experiment method is in the Supporting Information.
28. See Supporting Information.
29. Measurements of the concentration of 32 in plasma and brain were performed in mice following po administration at 32 mg/ kg. 32 was suspended in 0.5% methylcellulose and administered orally in a volume of 10 mL/kg. Plasma and brain were collected at 0.5 and 2 h after dosing, and the concentrations of 32 were measured using HPLC.
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