Discovery of 2-[(E)-2-(7-Fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine Hydrochloride as a Highly Selective PDE10A Inhibitor
Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptom...
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| Published in | Chemical & pharmaceutical bulletin Vol. 66; no. 3; pp. 243 - 250 |
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| Main Authors | , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Japan
The Pharmaceutical Society of Japan
2018
Pharmaceutical Society of Japan Japan Science and Technology Agency |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0009-2363 1347-5223 |
| DOI | 10.1248/cpb.c17-00783 |
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| Abstract | Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5. We transformed the afforded derivatives, which had weak inhibitory activity against PDE10A, and discovered stilbene as a PDE10A inhibitor. Brain penetration of this compound was improved by further conversion of N-containing heterocycles and their substituents. The afforded dimethylaminopyrimidine was effective for rat conditioned avoidance response (CAR) test; however, it did not exhibit good brain penetration. We performed in-depth optimization focusing on substituents of the quinoxaline ring, and produced 3-methyl-7-fluoro quinoxaline. This compound was the most effective in rat CAR test due to its strong PDE10A inhibitory activity and good pharmacokinetics. |
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| AbstractList | Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5. We transformed the afforded derivatives, which had weak inhibitory activity against PDE10A, and discovered stilbene as a PDE10A inhibitor. Brain penetration of this compound was improved by further conversion of N-containing heterocycles and their substituents. The afforded dimethylaminopyrimidine was effective for rat conditioned avoidance response (CAR) test; however, it did not exhibit good brain penetration. We performed in-depth optimization focusing on substituents of the quinoxaline ring, and produced 3-methyl-7-fluoro quinoxaline. This compound was the most effective in rat CAR test due to its strong PDE10A inhibitory activity and good pharmacokinetics. Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5. We transformed the afforded derivatives, which had weak inhibitory activity against PDE10A, and discovered stilbene as a PDE10A inhibitor. Brain penetration of this compound was improved by further conversion of N-containing heterocycles and their substituents. The afforded dimethylaminopyrimidine was effective for rat conditioned avoidance response (CAR) test; however, it did not exhibit good brain penetration. We performed in-depth optimization focusing on substituents of the quinoxaline ring, and produced 3-methyl-7-fluoro quinoxaline. This compound was the most effective in rat CAR test due to its strong PDE10A inhibitory activity and good pharmacokinetics. Graphical Abstract |
| Author | Miyoshi, Haruko Kimura, Mayumi Takedomi, Kei Watanabe, Yumi Kojima, Koki Omori, Kenji Taniguchi, Hiroyuki Sakamoto, Toshiaki Hongu, Mitsuya Kotera, Jun Kobayashi, Tamaki Kadoh, Yoichi Sasaki, Takashi Kawanishi, Eiji Matsumura, Takehiko Tanaka, Yoshihito Himiyama, Toshiyuki |
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| CitedBy_id | crossref_primary_10_1016_j_ejmech_2021_113155 crossref_primary_10_1248_cpb_c22_00357 crossref_primary_10_1016_j_bmc_2019_06_021 crossref_primary_10_1016_j_ejmech_2024_116386 crossref_primary_10_1021_acs_oprd_9b00068 crossref_primary_10_1016_j_bmc_2019_07_010 crossref_primary_10_4049_jimmunol_2001026 crossref_primary_10_1016_j_pbb_2019_172757 |
| Cites_doi | 10.1111/j.1460-9568.2005.03937.x 10.1016/j.neuropharm.2006.01.012 10.1016/j.juro.2012.03.115 10.1074/jbc.274.26.18438 10.1016/j.bmcl.2014.09.082 10.1016/j.bmc.2005.05.030 10.1046/j.1432-1327.1999.00963.x 10.1007/BF02465841 10.1074/jbc.M308471200 10.1111/j.1471-4159.2007.05152.x 10.1021/jm9015334 10.1021/jm3004976 10.1016/j.euroneuro.2007.08.002 10.1006/bbrc.1999.1013 10.1016/j.bmcl.2014.10.008 10.1161/01.RES.0000256354.95791.f1 |
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| References | 15) Sakamoto T., Koga Y., Hikota M., Matsuki K., Murakami M., Kikkawa K., Fujishige K., Kotera J., Omori K., Morimoto H., Yamada K., Bioorg. Med. Chem. Lett., 24, 5460–5465 (2014). 5) Kotera J., Sasaki T., Kobayashi T., Fujishige K., Yamashita Y., Omori K., J. Biol. Chem., 279, 4366–4375 (2004). 14) Sakamoto T., Koga Y., Hikota M., Matsuki K., Murakami M., Kikkawa K., Fujishige K., Kotera J., Omori K., Morimoto H., Yamada K., Bioorg. Med. Chem. Lett., 24, 5175–5180 (2014). 20) Takano Y., Shiga F., Asano J., Ando N., Uchiki H., Fukuchi K., Anraku T., Bioorg. Med. Chem., 13, 5841–5863 (2005). 23) Kawanishi E., Matsumura T., WO 2010027097 (2010). 2) Fujishige K., Kotera J., Michibata H., Yuasa K., Takebayashi S., Okumura K., Omori K., J. Biol. Chem., 274, 18438–18445 (1999). 6) Siuciak J. A., McCarthy S. A., Chapin D. S., Fujiwara R. A., James L. C., Williams R. D., Stock J. L., McNeish J. D., Strick C. A., Menniti F. S., Schmidt C. J., Neuropharamcology, 51, 374–385 (2006). 7) Sano H., Nagai Y., Miyakawa T., Shigemoto R., Yokoi M., J. Neurochem., 105, 546–556 (2008). 1) Omori K., Kotera J., Circ. Res., 100, 309–327 (2007). 11) Verhoest P. R., Chapin D. S., Corman M., Fonseca K., Harms J. F., Hou X., Marr E. S., Menniti F. S., Nelson F., O’Connor R., Pandit J., Proulx-LaFrance C., Schmidt A. W., Schmidt C. J., Suiciak J. A., Liras S., J. Med. Chem., 52, 5188–5196 (2009). 8) Rodefer J. S., Murphy E. R., Baxter M. G., Eur. J. Neurosci., 21, 1070–1076 (2005). 4) Fujishige K., Kotera J., Omori K., Eur. J. Biochem., 266, 1118–1127 (1999). 10) Chappie T. A., Helal C. J., Hou X., J. Med. Chem., 55, 7299–7331 (2012). 21) Shvachkin Y. P., Krasnoshchekova S. P., Nikitina A. M., Anokhina T. M., Pharm. Chem. J., 32, 621–621 (1998). 17) Yamada K., Matsuki K., Omori K., Kikkawa K., WO 2001083460 (2001). 9) Hebb A. L. O., Robertson H. A., Denovan-Wright E. M., Eur. Neuropsychopharm., 18, 339–363 (2008). 18) Kotera J., Fujishige K., Michibata H., Yuasa K., Kubo A., Nakamura Y., Omori K., Biochem. Pharmacol., 60, 1333–1341 (2000). 22) Morimoto H., Sakamoto T., Himiyama T., Kawanishi E., Matsumura T., WO 2010030027 (2010). 3) Kotera J., Fujishige K., Yuasa K., Omori K., Biochem. Biophys. Res. Commun., 261, 551–557 (1999). 19) The sequence of rat PDE10A was used as the amino acid number. 13) Kotera J., Mochida H., Inoue H., Noto T., Fujishige K., Sasaki T., Kobayashi T., Kojima K., Yee S., Yamada Y., Kikkawa K., Omori K., J. Urol., 188, 668–674 (2012). 12) Kunitomo J., Yoshikawa M., Fushimi M., Kawada A., Quinn J. F., Oki H., Kokubo H., Kondo M., Nakashima K., Kamiguchi N., Suzuki K., Kimura H., Taniguchi T., J. Med. Chem., 57, 9627–9643 (2014). 16) The full length amino acid sequence was obtained from Uniprot (http://www.uniprot.org/) and the catalytic domain was based on the annotation described in UniProt. Homology was calculated after amino acid sequence alignment in ClustalW. 11 22 12 23 13 14 15 16 17 18 19 1 2 3 4 5 6 7 8 9 20 10 21 |
| References_xml | – reference: 23) Kawanishi E., Matsumura T., WO 2010027097 (2010). – reference: 8) Rodefer J. S., Murphy E. R., Baxter M. G., Eur. J. Neurosci., 21, 1070–1076 (2005). – reference: 11) Verhoest P. R., Chapin D. S., Corman M., Fonseca K., Harms J. F., Hou X., Marr E. S., Menniti F. S., Nelson F., O’Connor R., Pandit J., Proulx-LaFrance C., Schmidt A. W., Schmidt C. J., Suiciak J. A., Liras S., J. Med. Chem., 52, 5188–5196 (2009). – reference: 20) Takano Y., Shiga F., Asano J., Ando N., Uchiki H., Fukuchi K., Anraku T., Bioorg. Med. Chem., 13, 5841–5863 (2005). – reference: 3) Kotera J., Fujishige K., Yuasa K., Omori K., Biochem. Biophys. Res. Commun., 261, 551–557 (1999). – reference: 5) Kotera J., Sasaki T., Kobayashi T., Fujishige K., Yamashita Y., Omori K., J. Biol. Chem., 279, 4366–4375 (2004). – reference: 18) Kotera J., Fujishige K., Michibata H., Yuasa K., Kubo A., Nakamura Y., Omori K., Biochem. Pharmacol., 60, 1333–1341 (2000). – reference: 15) Sakamoto T., Koga Y., Hikota M., Matsuki K., Murakami M., Kikkawa K., Fujishige K., Kotera J., Omori K., Morimoto H., Yamada K., Bioorg. Med. Chem. Lett., 24, 5460–5465 (2014). – reference: 19) The sequence of rat PDE10A was used as the amino acid number. – reference: 10) Chappie T. A., Helal C. J., Hou X., J. Med. Chem., 55, 7299–7331 (2012). – reference: 6) Siuciak J. A., McCarthy S. A., Chapin D. S., Fujiwara R. A., James L. C., Williams R. D., Stock J. L., McNeish J. D., Strick C. A., Menniti F. S., Schmidt C. J., Neuropharamcology, 51, 374–385 (2006). – reference: 14) Sakamoto T., Koga Y., Hikota M., Matsuki K., Murakami M., Kikkawa K., Fujishige K., Kotera J., Omori K., Morimoto H., Yamada K., Bioorg. Med. Chem. Lett., 24, 5175–5180 (2014). – reference: 2) Fujishige K., Kotera J., Michibata H., Yuasa K., Takebayashi S., Okumura K., Omori K., J. Biol. Chem., 274, 18438–18445 (1999). – reference: 16) The full length amino acid sequence was obtained from Uniprot (http://www.uniprot.org/) and the catalytic domain was based on the annotation described in UniProt. Homology was calculated after amino acid sequence alignment in ClustalW. – reference: 21) Shvachkin Y. P., Krasnoshchekova S. P., Nikitina A. M., Anokhina T. M., Pharm. Chem. J., 32, 621–621 (1998). – reference: 1) Omori K., Kotera J., Circ. Res., 100, 309–327 (2007). – reference: 9) Hebb A. L. O., Robertson H. A., Denovan-Wright E. M., Eur. Neuropsychopharm., 18, 339–363 (2008). – reference: 7) Sano H., Nagai Y., Miyakawa T., Shigemoto R., Yokoi M., J. Neurochem., 105, 546–556 (2008). – reference: 17) Yamada K., Matsuki K., Omori K., Kikkawa K., WO 2001083460 (2001). – reference: 12) Kunitomo J., Yoshikawa M., Fushimi M., Kawada A., Quinn J. F., Oki H., Kokubo H., Kondo M., Nakashima K., Kamiguchi N., Suzuki K., Kimura H., Taniguchi T., J. Med. Chem., 57, 9627–9643 (2014). – reference: 13) Kotera J., Mochida H., Inoue H., Noto T., Fujishige K., Sasaki T., Kobayashi T., Kojima K., Yee S., Yamada Y., Kikkawa K., Omori K., J. Urol., 188, 668–674 (2012). – reference: 4) Fujishige K., Kotera J., Omori K., Eur. J. Biochem., 266, 1118–1127 (1999). – reference: 22) Morimoto H., Sakamoto T., Himiyama T., Kawanishi E., Matsumura T., WO 2010030027 (2010). – ident: 17 – ident: 8 doi: 10.1111/j.1460-9568.2005.03937.x – ident: 18 – ident: 6 doi: 10.1016/j.neuropharm.2006.01.012 – ident: 13 doi: 10.1016/j.juro.2012.03.115 – ident: 2 doi: 10.1074/jbc.274.26.18438 – ident: 12 – ident: 14 doi: 10.1016/j.bmcl.2014.09.082 – ident: 20 doi: 10.1016/j.bmc.2005.05.030 – ident: 4 doi: 10.1046/j.1432-1327.1999.00963.x – ident: 21 doi: 10.1007/BF02465841 – ident: 19 – ident: 16 – ident: 5 doi: 10.1074/jbc.M308471200 – ident: 7 doi: 10.1111/j.1471-4159.2007.05152.x – ident: 11 doi: 10.1021/jm9015334 – ident: 10 doi: 10.1021/jm3004976 – ident: 9 doi: 10.1016/j.euroneuro.2007.08.002 – ident: 3 doi: 10.1006/bbrc.1999.1013 – ident: 15 doi: 10.1016/j.bmcl.2014.10.008 – ident: 1 doi: 10.1161/01.RES.0000256354.95791.f1 – ident: 22 – ident: 23 |
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| Snippet | Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the... |
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| SubjectTerms | Animals Avoidance behavior Avoidance Learning - drug effects Binding Sites Brain conditioned avoidance response (CAR) Conditioning Crystallography, X-Ray Cyclic AMP Cyclic GMP Drug Evaluation, Preclinical Erectile dysfunction Homology Hydrolase Inhibitors Inhibitory Concentration 50 Mental disorders Molecular Dynamics Simulation Neostriatum Neurons Optimization Penetration Pharmacokinetics Pharmacology Phosphodiesterase phosphodiesterase (PDE) 10A Phosphodiesterase Inhibitors - chemistry Phosphodiesterase Inhibitors - metabolism Phosphodiesterase Inhibitors - pharmacology Phosphoric Diester Hydrolases - chemistry Phosphoric Diester Hydrolases - metabolism Psychosis pyrimidine Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacology Quinoxaline Quinoxalines Quinoxalines - chemical synthesis Quinoxalines - chemistry Quinoxalines - pharmacology Rats Rodents Schizophrenia Signs and symptoms Spiny neurons Stilbene Structure-Activity Relationship Tetrahydro-2H-pyran |
| Title | Discovery of 2-[(E)-2-(7-Fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine Hydrochloride as a Highly Selective PDE10A Inhibitor |
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| ispartofPNX | Chemical and Pharmaceutical Bulletin, 2018/03/01, Vol.66(3), pp.243-250 |
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