Fragment-Based Discovery of Pyrimido[1,2-b]indazole PDE10A Inhibitors

被引：23

作者：

Chino, Ayaka ^{[1
]}

Seo, Ryushi ^{[1
]}

Amano, Yasushi ^{[1
]}

Namatame, Ichiji ^{[1
]}

Hamaguchi, Wataru ^{[1
]}

Honbou, Kazuya ^{[1
]}

Mihara, Takuma ^{[1
]}

Yamazaki, Mayako ^{[1
]}

Tomishima, Masaki ^{[1
]}

Masuda, Naoyuki ^{[1
]}

机构：

[1] Astellas Pharma Inc, Drug Discovery Res, 21 Miyukigaoka, Tsukuba, Ibaraki 3058585, Japan

来源：

CHEMICAL & PHARMACEUTICAL BULLETIN | 2018年 / 66卷 / 03期

关键词：

phosphodiesterase10A inhibitor; fragment-based drug discovery; schizophrenia; combinatorial synthesis; pyrimido[1,2-b]indazole; PHOSPHODIESTERASE 10A INHIBITORS; PHARMACOLOGICAL EVALUATION; LEAD DISCOVERY; DESIGN; DERIVATIVES; POTENT; IDENTIFICATION; SCHIZOPHRENIA;

D O I：

10.1248/cpb.c17-00836

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In this study, we report the identification of potent pyrimidoindazoles as phosphodiesterase10A (PDE10A) inhibitors by using the method of fragment-based drug discovery (FBDD). The pyrazolopyridine derivative 2 was found to be a fragment hit compound which could occupy a part of the binding site of PDE10A enzyme by using the method of the X-ray co-crystal structure analysis. On the basis of the crystal structure of compound 2 and PDE10A protein, a number of compounds were synthesized and evaluated, by means of structure activity relationship (SAR) studies, which culminated in the discovery of a novel pyrimidoindazole derivative 13 having good physicochemical properties.

引用

页码：286 / 294

页数：9

共 35 条

[21] Discovery of pyrazolopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia [J].

Raheem, Izzat T. ;

Schreier, John D. ;

Fuerst, Joy ;

Gantert, Liza ;

Hostetler, Eric D. ;

Huszar, Sarah ;

Joshi, Aniket ;

Kandebo, Monika ;

Kim, Somang H. ;

Li, Jing ;

Ma, Bennett ;

McGaughey, Georgia ;

Sharma, Sujata ;

Shipe, William D. ;

Uslaner, Jason ;

Vandeveer, George H. ;

Yan, Youwei ;

Renger, John J. ;

Smith, Sean M. ;

Coleman, Paul J. ;

Cox, Christopher D. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2016, 26 (01) :126-132

[22] Fragment library design, synthesis and expansion: nurturing a synthesis and training platform [J].

Ray, Peter C. ;

Kiczun, Michael ;

Huggett, Margaret ;

Lim, Andrew ;

Prati, Federica ;

Gilbert, Ian H. ;

Wyatt, Paul G. .

DRUG DISCOVERY TODAY, 2017, 22 (01) :43-56

[23] Current and novel approaches to the drug treatment of schizophrenia [J].

Rowley, M ;

Bristow, LJ ;

Hutson, PH .

JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (04) :477-501

[24] Preclinical characterization of selective phosphodiesterase 10A inhibitors: A new therapeutic approach to the treatment of schizophrenia [J].

Schmidt, C. J. ;

Chapin, D. S. ;

Cianfrogna, J. ;

Corman, M. L. ;

Hajos, M. ;

Harms, J. F. ;

Hoffman, W. E. ;

Lebel, L. A. ;

McCarthy, S. A. ;

Nelson, R. ;

Proulx-LaFrance, C. ;

Majchrzak, M. J. ;

Ramirez, A. D. ;

Schmidt, K. ;

Seymour, P. A. ;

Siuciak, J. A. ;

Tingley, F. D., III ;

Williams, R. D. ;

Verhoest, P. R. ;

Menniti, F. S. .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2008, 325 (02) :681-690

[25] The Phosphodiesterase 10A Selective Inhibitor TAK-063 Improves Cognitive Functions Associated with Schizophrenia in Rodent Modelss [J].

Shiraishi, Eri ;

Suzuki, Kazunori ;

Harada, Akina ;

Suzuki, Noriko ;

Kimura, Haruhide .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2016, 356 (03) :587-595

[26] A Possible Role for the Striatum in the Pathogenesis of the Cognitive Symptoms of Schizophrenia [J].

Simpson, Eleanor H. ;

Kellendonk, Christoph ;

Kandel, Eric .

NEURON, 2010, 65 (05) :585-596

[27] The novel phosphodiesterase 10A inhibitor THPP-1 has antipsychotic-like effects in rat and improves cognition in rat and rhesus monkey [J].

Smith, Sean M. ;

Uslaner, Jason M. ;

Cox, Christopher D. ;

Huszar, Sarah L. ;

Cannon, Christopher E. ;

Vardigan, Joshua D. ;

Eddins, Donnie ;

Toolan, Dawn M. ;

Kandebo, Monika ;

Yao, Lihang ;

Raheem, Izzat T. ;

Schreier, John D. ;

Breslin, Michael J. ;

Coleman, Paul J. ;

Renger, John J. .

NEUROPHARMACOLOGY, 2013, 64 :215-223

[28] Isolation and characterization of a dual-substrate phosphodiesterase gene family: PDE10A [J].

Soderling, SH ;

Bayuga, SJ ;

Beavo, JA .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (12) :7071-7076

[29] Schizophrenia, "just the facts" 4. Clinical features and conceptualization [J].

Tandon, Rajiv ;

Nasrallah, Henry A. ;

Keshavan, Matcheri S. .

SCHIZOPHRENIA RESEARCH, 2009, 110 (1-3) :1-23

[30] Identification of a Brain Penetrant PDE9A Inhibitor Utilizing Prospective Design and Chemical Enablement as a Rapid Lead Optimization Strategy [J].

Verhoest, Patrick R. ;

Proulx-Lafrance, Caroline ;

Corman, Michael ;

Chenard, Lois ;

Helal, Christopher J. ;

Hou, Xinjun ;

Kleiman, Robin ;

Liu, Shenping ;

Marr, Eric ;

Menniti, Frank S. ;

Schmidt, Christopher J. ;

Vanase-Frawley, Michelle ;

Schmidt, Anne W. ;

Williams, Robert D. ;

Nelson, Frederick R. ;

Fonseca, Kari R. ;

Liras, Spiros .

JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (24) :7946-7949

← 1 2 3 4 →