Discovery of a novel, potent, and orally active nonpeptide antagonist of the human luteinizing hormone-releasing hormone (LHRH) receptor [3]

Journal of Medicinal Chemistry

Volumn 41, Issue 22, 1998, Pages 4190-4195

  Cho, Nobuo ^a   Harada, Masataka ^a   Imaeda, Toshihiro ^a   Imada, Takashi ^a   Matsumoto, Hirokazu ^a   Hayase, Yoji ^a   Sasaki, Satoshi ^a   Furuya, Shuichi ^a   Suzuki, Nobuhiro ^a   Okubo, Shoichi ^a   Ogi, Kazuhiro ^a   Endo, Satoshi ^a   Onda, Haruo ^a   Fujino, Masahiko ^a  

^a TAKEDA PHARMACEUTICAL COMPANY LIMITED   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

3 (N BENZYL N METHYLAMINOMETHYL) 7 (2,6 DIFLUOROBENZYL) 4,7 DIHYDRO 2 (4 ISOBUTYRYLAMINOPHENYL) 4 OXOTHIENO[2,3 B]PYRIDINE 5 CARBOXYLIC ACID ISOPROPYL ESTER; GONADORELIN ANTAGONIST; GONADORELIN RECEPTOR; LEUPRORELIN; LUTEINIZING HORMONE; THIENO[2,3 B]PYRIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ADENOHYPOPHYSIS; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; CASTRATION; CHO CELL; CONTROLLED STUDY; DRUG DESIGN; DRUG EFFICACY; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG SYNTHESIS; GONADORELIN RELEASE; LETTER; LUTEINIZING HORMONE BLOOD LEVEL; LUTEINIZING HORMONE RELEASE; MALE; MONKEY; NONHUMAN; ORAL DRUG ADMINISTRATION; RAT;

ANIMALS; CHO CELLS; CLONING, MOLECULAR; CRICETINAE; HUMANS; LUTEINIZING HORMONE; MACACA FASCICULARIS; MALE; MODELS, MOLECULAR; PITUITARY GLAND, ANTERIOR; PYRIDONES; RATS; RATS, WISTAR; RECEPTORS, LHRH; THIOPHENES;

EID: 15444355594     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9803673     Document Type: Letter

References (33)

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19. -)CHO cells using calcium phosphate-mediated transfection. The transfected CHO cells were cultured in a selection medium, and a single colony expressing high levels of the receptor was isolated.
20. 50)], where %SPB is specific binding as a percentage of maximum specific binding, n is a pseudo-Hill constant, and C is the concentration of a test compound.
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25. 3, 0.25 mM phenylmethanesulfonyl fluoride, 10 U/mL aprotinin, 1 μg/mL pepstatin A, 20 μg/mL leupeptin, and 100 μg/mL phosphoramidon, pH 7.5) and homogenized using a Polytron homogenizer. After the resulting homogenate was centrifuged for 15 min at 700g, the supernatant was centrifuged for 1 h at 100000g. The pellet resuspended in 10 mL of assay buffer Awas centrifuged for 1 h at 100000g. The membrane fraction obtained as a pellet was suspended in 10 mL of assay buffer A and was stored at -80 °C. The preparation of monkey pituitary membranes was performed in a similar manner.
26. 2-adrenergic receptor. Figure 2, left, shows a three-dimensional model of the human LHRH receptor viewed from the extracellular side. Transmembrane helices are depicted as green ribbons, and residues constituting the putative ligand-binding pocket are shown with CPK models. Colors used for CPK models are red for acidic residues, cyan for basic residues, magenta for other hydrophilic residues, and yellow for hydrophobia residues.
27. 2-adrenergic receptor. Figure 2, left, shows a three-dimensional model of the human LHRH receptor viewed from the extracellular side. Transmembrane helices are depicted as green ribbons, and residues constituting the putative ligand-binding pocket are shown with CPK models. Colors used for CPK models are red for acidic residues, cyan for basic residues, magenta for other hydrophilic residues, and yellow for hydrophobia residues.
28. The binding mode of T-98475 (1) to the modeled receptor was investigated with the automated docking program DOCK 3.5; see: (a) Shoichet, B. K.; Bodian, D. L.; Kuntz, I. D. Molecular Docking Using Shape Descriptors. J. Comput. Chem. 1992, 13, 380-397. (b) Meng, E. C.; Shoichet, B. K.; Kuntz, I. D. Automated Docking with Grid-Based Energy Evaluation. J. Comput. Chem. 1992, 23, 505-524. (c) Meng, E. C.; Gschwend, D. A.; Blaney, J. M.; Kuntz, I. D. Orientational Sampling and Rigid-Body Minimization in Molecular Docking. Proteins 1993, 17, 266-278. Flexibility of the compound was taken into account by searching the conformational database prepared for T-98475 (1). Figure 2, right (the highest scoring mode), shows a detailed view of the interaction between the human LHRH receptor (thin bonds) and T-98475 (1) (thick bonds). T-98475 (1) is drawn with atoms in light green (carbon), cyan (nitrogen), red (oxygen), sulfur (yellow), and dark green (fluorine). A solvent-accessible surface of the receptor molecule is shown as purple dots. Asp302 in the seventh transmembrane domain is drawn as a ball-and-stick model.
29. The binding mode of T-98475 (1) to the modeled receptor was investigated with the automated docking program DOCK 3.5; see: (a) Shoichet, B. K.; Bodian, D. L.; Kuntz, I. D. Molecular Docking Using Shape Descriptors. J. Comput. Chem. 1992, 13, 380-397. (b) Meng, E. C.; Shoichet, B. K.; Kuntz, I. D. Automated Docking with Grid-Based Energy Evaluation. J. Comput. Chem. 1992, 23, 505-524. (c) Meng, E. C.; Gschwend, D. A.; Blaney, J. M.; Kuntz, I. D. Orientational Sampling and Rigid-Body Minimization in Molecular Docking. Proteins 1993, 17, 266-278. Flexibility of the compound was taken into account by searching the conformational database prepared for T-98475 (1). Figure 2, right (the highest scoring mode), shows a detailed view of the interaction between the human LHRH receptor (thin bonds) and T-98475 (1) (thick bonds). T-98475 (1) is drawn with atoms in light green (carbon), cyan (nitrogen), red (oxygen), sulfur (yellow), and dark green (fluorine). A solvent-accessible surface of the receptor molecule is shown as purple dots. Asp302 in the seventh transmembrane domain is drawn as a ball-and-stick model.
30. The binding mode of T-98475 (1) to the modeled receptor was investigated with the automated docking program DOCK 3.5; see: (a) Shoichet, B. K.; Bodian, D. L.; Kuntz, I. D. Molecular Docking Using Shape Descriptors. J. Comput. Chem. 1992, 13, 380-397. (b) Meng, E. C.; Shoichet, B. K.; Kuntz, I. D. Automated Docking with Grid-Based Energy Evaluation. J. Comput. Chem. 1992, 23, 505-524. (c) Meng, E. C.; Gschwend, D. A.; Blaney, J. M.; Kuntz, I. D. Orientational Sampling and Rigid-Body Minimization in Molecular Docking. Proteins 1993, 17, 266-278. Flexibility of the compound was taken into account by searching the conformational database prepared for T-98475 (1). Figure 2, right (the highest scoring mode), shows a detailed view of the interaction between the human LHRH receptor (thin bonds) and T-98475 (1) (thick bonds). T-98475 (1) is drawn with atoms in light green (carbon), cyan (nitrogen), red (oxygen), sulfur (yellow), and dark green (fluorine). A solvent-accessible surface of the receptor molecule is shown as purple dots. Asp302 in the seventh transmembrane domain is drawn as a ball-and-stick model.
31. Flanagan, C. A.; Becker, I. I.; Davidson, J. S.; Wakefield, I. K.; Zhou, W.; Sealfon, S. C.; Millar, R. P. Glutamate 301 of the Mouse Gonadotropin-Releasing Hormone Receptor Confers Specificity for Arginine 8 of Mammalian Gonadotropin-Releasing Hormone. J. Biol. Chem. 1994, 269, 22636-22641.
32. 5 cells) were washed twice and then incubated in 0.4 mL of the assay buffer with samples (conditioned medium of monkey pituitary cells or monkey plasma) to be tested at 37 °C for 2 h. Equine LH (Sigma) was used as a standard. Then, the medium was harvested, and testosterone concentration was measured with radioimmunoassay (CIS Diagnostics, Ltd., Sakura, Chiba, Japan).
33. 25