- Discovery of a First-in-Class Gut-Restricted RET Kinase Inhibitor as a Clinical Candidate for the Treatment of IBS
-
Abdominal pain and abnormal bowel habits represent major symptoms for irritable bowel syndrome (IBS) patients that are not adequately managed. Although the etiology of IBS is not completely understood, many of the functions of the gastrointestinal (GI) tract are regulated by the enteric nervous system (ENS). Inflammation or stress-induced expression of growth factors or cytokines may lead to hyperinnervation of visceral afferent neurons in GI tract and contribute to the pathophysiology of IBS. Rearranged during transfection (RET) is a neuronal growth factor receptor tyrosine kinase critical for the development of the ENS as exemplified by Hirschsprung patients who carry RET loss-of-function mutations and lack normal colonic innervation leading to colonic obstruction. Similarly, RET signaling in the adult ENS maintains neuronal function by contributing to synaptic formation, signal transmission, and neuronal plasticity. Inhibition of RET in the ENS represents a novel therapeutic strategy for the normalization of neuronal function and the symptoms of IBS patients. Herein, we describe our screening effort and subsequent structure-activity relationships (SARs) in optimizing potency, selectivity, and mutagenicity of the series, which led to the discovery of a first-in-class, gut-restricted RET kinase inhibitor, 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (15, GSK3179106), as a clinical candidate for the treatment of IBS. GSK3179106 is a potent, selective, and gut-restricted pyridone hinge binder small molecule RET kinase inhibitor with a RET IC50 of 0.3 nM and is efficacious in vivo.
- Schenck Eidam, Hilary,Russell, John,Raha, Kaushik,Demartino, Michael,Qin, Donghui,Guan, Huiping Amy,Zhang, Zhiliu,Zhen, Gong,Yu, Haiyu,Wu, Chengde,Pan, Yan,Joberty, Gerard,Zinn, Nico,Laquerre, Sylvie,Robinson, Sharon,White, Angela,Giddings, Amanda,Mohammadi, Ehsan,Greenwood-Van Meerveld, Beverly,Oliff, Allen,Kumar, Sanjay,Cheung, Mui
-
supporting information
p. 623 - 628
(2018/07/25)
-
- BIARYL DERIVATIVE AS GPR120 AGONIST
-
The present invention relates to a biaryl derivative expressed by the chemical formula 1, a method for producing the biaryl derivative, a pharmaceutical composition comprising same, and use of same, the biaryl derivative expressed by the chemical formula 1, as a GPR120 agonist, promoting GLP-1 generation in the gastro-intestinal tract, reducing insulin resistance in the liver, muscles and the like from anti-inflammatory activity in the macrophage, pancreatic cells and the like, and allowing effective use in prevention or treatment of inflammation or metabolic diseases such as diabetes, complications from diabetes, obesity, non-alcoholic fatty liver disease, fatty liver disease, and osteoporosis.
- -
-
Paragraph 0346; 0358
(2017/11/17)
-
- CRYSTALLINE FORMS OF 2-(4-(4-ETHOXY-6-OXO-1,6-DIHYDROPYRIDIN-3-YL)-2-FLUOROPHENYL)-N-(5-(1,1,1-TRIFLUORO-2-METHYLPROPAN-2-YL)ISOXAZOL-3-YL)ACETAMIDE
-
Disclosed are novel crystalline forms of 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin- 3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide and pharmaceutical compositions containing the same. Also disclosed are processes for the preparation thereof and methods for use thereof.
- -
-
Page/Page column 36
(2016/04/20)
-
- PYRIDONE DERIVATIVES AS REARRANGED DURING TRANSFECTION (RET) KINASE INHIBITORS
-
This invention relates to novel compounds which are inhibitors of the Rearranged during Transfection (RET) kinase, to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy, alone or in combination, for the normalization of gastrointestinal sensitivity, motility and/or secretion and/or abdominal disorders or diseases and/or treatment related to diseases related to RET dysfunction or where modulation of RET activity may have therapeutic benefit including but not limited to all classifications of irritable bowel syndrome (IBS) including diarrhea-predominant, constipation-predominant or alternating stool pattern, functional bloating, functional constipation, functional diarrhea, unspecified functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disorders, functional gastroduodenal disorders, functional anorectal pain, inflammatory bowel disease, proliferative diseases such as non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer, medullary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, papillary thyroid cancer, brain tumors, peritoneal cavity cancer, solid tumors, other lung cancer, head and neck cancer, gliomas, neuroblastomas, Von Hippel-Lindau Syndrome and kidney tumors, breast cancer, fallopian tube cancer, ovarian cancer, transitional cell cancer, prostate cancer, cancer of the esophagus and gastroesophageal junction, biliary cancer, adenocarcinoma, and any malignancy with increased RET kinase activity.
- -
-
Page/Page column 50
(2016/06/01)
-
- TETRAHYDROTHIAZEPINE DERIVATIVE
-
The present invention relates to a compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof having an excellent effect of inhibiting 11β-hydroxysteroid dehydrogenase type 1: General formula (I) wherein R1 represents a phenyl group that may be substituted with 1 to 5 group(s) independently selected from substituent group A or a heterocyclic group that may be substituted with 1 to 4 group(s) independently selected from substituent group A; R2 independently represents a halogen atom or a C1-C6 alkyl group; n represents an integer of 0 to 2; and substituent group A represents the group consisting of halogen atoms, C1-C6 alkyl groups, and so forth.
- -
-
Paragraph 0188
(2014/03/24)
-
- PYRIDINE DERIVATIVES AS REARRANGED DURING TRANSFECTION (RET) KINASE INHIBITORS
-
This invention relates to novel compounds which are inhibitors of the Rearranged during Transfection (RET) kinase, to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy, alone or in combination, for the normalization of gastrointestinal sensitivity, motility and/or secretion and/or abdominal disorders or diseases and/or treatment related to diseases related to RET dysfunction or where modulation of RET activity may have therapeutic benefit including but not limited to all classifications of irritable bowel syndrome (IBS) including diarrhea-predominant, constipation-predominant or alternating stool pattern, functional bloating, functional constipation, functional diarrhea, unspecified functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disorders, functional gastroduodenal disorders, functional anorectal pain, inflammatory bowel disease, proliferative diseases such as non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer, medullary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, papillary thyroid cancer, brain tumors, peritoneal cavity cancer, solid tumors, other lung cancer, head and neck cancer, gliomas, neuroblastomas, Von Hippel-Lindau Syndrome and kidney tumors, breast cancer, fallopian tube cancer, ovarian cancer, transitional cell cancer, prostate cancer, cancer of the esophagus and gastroesophageal junction, biliary cancer, adenocarcinoma, and any malignancy with increased RET kinase activity.
- -
-
Page/Page column 54; 44; 56; 57
(2014/09/29)
-
- NOVEL COMPOUNDS AS REARRANGED DURING TRANSFECTION (RET) INHIBITORS
-
This invention relates to novel compounds which are inhibitors of the Rearranged during Transfection (RET) kinase, to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy, alone or in combination, for the normalization of gastrointestinal sensitivity, motility and/or secretion and/or abdominal disorders or diseases and/or treatment related to diseases related to RET dysfunction or where modulation of RET activity may have therapeutic benefit including but not limited to all classifications of irritable bowel syndrome (IBS) including diarrhea-predominant, constipation-predominant or alternating stool pattern, functional bloating, functional constipation, functional diarrhea, unspecified functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disorders, functional gastroduodenal disorders, functional anorectal pain, inflammatory bowel disease, proliferative diseases such as non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer, medullary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, papillary thyroid cancer, brain tumors, peritoneal cavity cancer, solid tumors, other lung cancer, head and neck cancer, gliomas, neuroblastomas, Von Hippel-Lindau Syndrome and kidney tumors, breast cancer, fallopian tube cancer, ovarian cancer, transitional cell cancer, prostate cancer, cancer of the esophagus and gastroesophageal junction, biliary cancer, adenocarcinoma, and any malignancy with increased RET kinase activity.
- -
-
Paragraph 0233; 0234
(2014/09/30)
-
- 8-ETHYL-6-(ARYL)PYRIDO [2,3-D]PYRIMIDIN-7(8H) -ONES FOR THE TREATMENT OF NERVOUS SYSTEM DISORDERS AND CANCER
-
Provided herein are PAK inhibitors and methods of utilizing PAK inhibitors for the treatment of CNS disorders such as neuropsychiatric disorders or neurofibromatosis. Also described herein are methods of utilizing PAK inhibitors for the treatment of cancer.
- -
-
-
- FATTY ACID SYNTHASE INHIBITORS
-
This invention relates to spirocyclic piperidines according to Formula (I) and the use of spirocyclic piperidines for the modulation, notably the inhibition of the activity or function of fatty acid synthase (FAS). Suitably, the present invention relates to the use of spirocyclic piperidines in the treatment of cancer.
- -
-
Page/Page column 93
(2013/03/26)
-
- CYCLOALKYLNITRILE PYRAZOLE CARBOXAMIDES AS JANUS KINASE INHIBITORS
-
Cycloalkylnitrile pyrazole carboxamides as JAK inhibitors useful for the treatment of JAK-mediated diseases such as rheumatoid arthritis, asthma, COPD and cancer are provided.
- -
-
Page/Page column 100
(2013/04/10)
-
- C-LINKED HYDROXAMIC ACID DERIVATIVES USEFUL AS ANTIBACTERIAL AGENTS
-
The present invention is directed to a new class of hydroxamic acid derivatives, their use as LpxC inhibitors, and more specifically their use to treat bacterial infections.
- -
-
Page/Page column 44
(2011/05/05)
-
- COMPOUNDS WHICH POTENTIATE AMPA RECEPTOR AND USES THEREOF IN MEDICINE
-
Compounds of formula (I), and salts and solvates thereof are provided: Processes for preparation, pharmaceutical compositions, and uses thereof as a medicament, for example in the treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function, such as schizophrenia or cognition impairment, are also disclosed.
- -
-
Page/Page column 23
(2010/06/16)
-
- PYRIDONE COMPOUND
-
An active ingredient is a compound represented by the general formula [I]: [wherein R1 and R2 represent a lower alkyl group, a C3-6 cycloalkyl group or the like, X1 and X2 represent methine, an Ar-Ys
- -
-
Page/Page column 33
(2010/11/30)
-
- NEW OXABISPIDINE COMPOUNDS FOR THE TREATMENT OF CARDIAC ARRHYTHMIAS
-
There is provided compounds of formula I, [Chemical formula should be inserted here. Please see paper copy] wherein R1 to R4 , R41 to R46 and Z have meanings given in the description, which are useful in the prophylaxis and in the treatment of arrhythmias, in particular atrial and ventricular arrhythmias
- -
-
Page/Page column 95
(2010/11/27)
-
- TISSUE FACTOR PRODUCTION INHIBITOR
-
A medicament which has an activity of inhibiting production of tissue factor and comprises an LXR ligand as an active ingredient; and a medicament for treatment and/or prophylaxis of vascular restenosis following angioplasty, endarterectomy, percutaneous transluminal coronary angioplasty (PTCA) or stent implantation, or treatment and/or prophylaxis of blood coagulation diseases, diseases induced by platelet aggregation including stable or unstable angina pectoris, cardiovascular and cerebrovascular diseases including thromboembolism formation diseases accompanying diabetes, rethrombosis following thrombolysis, cerebral ischemic attack, infarction, stroke, ischemia-derived dementia, peripheral artery disease, thromboembolism formation diseases during use of an aorta-coronary artery bypass, glomerulosclerosis, renal embolism, tumor or cancer metastasis, which comprises an LXR ligand as an active ingredient.
- -
-
Page/Page column 104
(2010/11/26)
-
- BENZENE COMPOUND HAVING 2 OR MORE SUBSTITUENTS
-
A superior LXR modulator is provided. A compound represented by the general formula (I): [wherein R1: -COR9 (wherein R9: alkyl, optionally substituted alkoxy or optionally substituted amino); R2: H, OH, alkoxy, optionally substituted amino, etc.; R3: H, optionally substituted alkyl, cycloalkyl, optionally substituted alkoxy, optionally substituted amino, halogeno, etc.; R4 and R5: H, optionally substituted alkyl, halogeno, etc.; R6 and R7: H, alkyl; R8: -X2R10 [wherein R10: -COR11 (wherein R11 : OH, optionally substituted alkoxy, optionally substituted amino, etc.), -SO2R12 (wherein R12: optionally substituted alkyl, optionally substituted amino, etc.), tetrazol-5-yl, etc.; X2: single bond, optionally substituted alkylene, etc.]; X1: -NH-, -O-, -S-, etc.; Y1: optionally substituted phenyl, optionally substituted 5- to 6-membered aromatic heterocyclyl; Y2: optionally substituted aryl, optionally substituted heterocyclyl, etc.] and the like is provided.
- -
-
-
- Allosteric inhibitors of hepatitis C polymerase: Discovery of potent and orally bioavailable carbon-linked dihydropyrones
-
The discovery and optimization of a novel class of carbon-linked dihydropyrones as allosteric HCV NS5B polymerase inhibitors are presented. Replacement of the sulfur linker atom with carbon reduced compound acidity and greatly increased cell permeation. F
- Li, Hui,Linton, Angelica,Tatlock, John,Gonzalez, Javier,Borchardt, Allen,Abreo, Mel,Jewell, Tanya,Patel, Leena,Drowns, Matthew,Ludlum, Sarah,Goble, Mike,Yang, Michele,Blazel, Julie,Rahavendran, Ravi,Skor, Heather,Shi, Stephanie,Lewis, Cristina,Fuhrman, Sheila
-
p. 3969 - 3972
(2008/02/11)
-
- BENZENE COMPOUND HAVING 2 OR MORE SUBSTITUENTS
-
Disclosed is an excellent LXR modulator. Specifically disclosed is a compound represented by the general formula (I) below or the like. (I) [In the formula, R1 represents a -COR9 (wherein R9 represents an alkyl, optionally substituted alkoxy or optionally substituted amino); R2 represents an H, OH, alkoxy, optionally substituted amino or the like; R3 represents an H, optionally substituted alkyl, cycloalkyl, optionally substituted alkoxy, optionally substituted amino, halogeno or the like; R4 and R5 respectively represent an H, optionally substituted alkyl, halogeno or the like; R6 and R7 respectively represent an H or alkyl; R8 represents a -X2R10 [wherein R10 represents a -COR11 (wherein R11 represents an OH, optionally substituted alkoxy, optionally substituted amino or the like), -SO2R12 (wherein R12 represents an optionally substituted alkyl, optionally substituted amino or the like), tetrazole-5-yl or the like; and X2 represents a single bond, optionally substituted alkylene or the like]; X1 represents an -NH-, -O-, -S- or the like; Y1 represents an optionally substituted phenyl or optionally substituted 5-membered or 6-membered aromatic heterocyclyl; and Y2 represents an optionally substituted aryl, substituted heterocyclyl or the like.]
- -
-
Page/Page column 177
(2010/11/08)
-
- SUBSTITUTED INDOLE COMPOUND
-
Disclosed is an excellent LXR modulator. A compound represented by the general formula (I): (I) wherein R1, R2, R3 and R4: H, an alkyl which may be substituted, OH, an alkoxy which may be substituted, an amino which may be substituted, a halogeno, a phenyl or the like; R5: H or an alkyl; R6: -COR8 (wherein R8: an alkoxy which may be substituted, a phenyloxy which may be substituted, an amino which may be substituted, or the like), -SO2R9 (wherein R9: an alkyl which may be substituted, a phenyl which may be substituted or a heterocyclyl which may be substituted), or an alkyl which may be substituted; R7: -X2R10 [wherein R10: -COR11 (where R11: OH, an alkoxy which may be substituted or an amino which may be substituted), -SO2R12 (where R12: an alkyl which may be substituted or amino which may be substituted), -N(R13)COR14 (where R13: H or an alkyl which may be substituted; R14: H or an alkyl which may be substituted), -N(R13)SO2R15 (where R13: as defined above; R15: an alkyl which may be substituted) or tetrazol-5-yl; and X2: a single bond or an alkylene which may be substituted]; X1: a methylene which may be substituted; Y1: a phenyl which may be substituted or a heterocyclyl which may be substituted; and Y2: an aryl which may be substituted, a heterocyclyl which may be substituted or the like], or the like.
- -
-
Page/Page column 165
(2010/11/24)
-
- Compositions and methods of treating cell proliferation disorders
-
The invention relates to compounds and methods for treating cell proliferation disorders.
- -
-
Page/Page column 76
(2008/06/13)
-
- Development of a synthetic process towards a hepatitis C polymerase inhibitor
-
The synthesis of 2-(4-{2-[(2R)-2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4] triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl] -ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile (1) on multikilogram scale is described. Initial synthesis
- Camp, David,Matthews, Chris F.,Neville, Sean T.,Rouns, Michael,Scott, Robert W.,Truong, Yen
-
p. 814 - 821
(2012/12/22)
-
- INHIBITORS OF HEPATITIS C VIRUS RNA-DEPENDENT RNA POLYMERASE, AND COMPOSITIONS AND TREATMENTS USING THE SAME
-
The present invention provides compounds of formula (4), and their pharmaceutically acceptable salts and solvates, which are useful as inhibitors of the Hepatitis C virus (HCV) polymerase enzyme and are also useful for the treatment of HCV infections in HCV-infected mammals. The present invention also provides pharmaceutical compositions comprising compounds of formula (4), their pharmaceutically acceptable salts and solvates. Furthermore, the present invention provides intermediate compounds and methods useful in the preparation of compounds of formula (4).
- -
-
Page/Page column 172
(2008/06/13)
-
- Monofluoroalkyl derivatives
-
The present invention provides certain monofluoroalkyl derivatives useful for potentiating glutamate receptor function in a mammal and therefore, useful for treating a wide variety of conditions, such as psychiatric and neurological disorders.
- -
-
Page/Page column 84-85
(2010/10/20)
-
- Inhibitors of hepatitis C virus RNA-dependent RNA polymerase, and compositions and treatments using the same
-
The invention relates to compounds of the formula 1 and to pharmaceutically acceptable salts, solvates, prodrugs and metabolites thereof, wherein W, Z, R1 and R2, are as defined herein. The invention also relates to methods of treating Hepatitis C virus in mammals by administering the compounds of formula 1, and to pharmaceutical compositions for treating such disorders, which contain the compounds of formula 1. The invention also relates to methods of preparing the compounds of formula 1.
- -
-
Page/Page column 58
(2008/06/13)
-
- Method of treating stroke
-
The present invention provides a method of treating stroke in a patient comprising administering to said patient an effective amount of a compound of the formula: or a pharmaceutically acceptable salt thereof.
- -
-
-
- INHIBITORS OF HEPATITIS C VIRUS RNA-DEPENDENT RNA POLYMERASE, AND COMPOSITIONS AND TREATMENTS USING THE SAME
-
The invention relates to compounds of the formula (I) and to pharmaceutically acceptable salts, solvates, prodrugs and metabolites thereof, wherein W, Z, R1and R2, are as defined herein. The invention also relates to methods of treating Hepatitis C virus in mammals by administering the compounds of formula (I), and to pharmaceutical compositions for treating such disorders, which contain the compounds of formula (I). The invention also relates to methods of preparing the compounds of formula (I).
- -
-
Page 111-112
(2008/06/13)
-
- PYRAZOLE DERIVATIVES AS ANGIOTENSIN II ANTAGONISTS
-
Compounds of general formula I and their salts and solvates are angiotensin II receptor antagonists and as such are useful in the treatment of hypertension, congestive heart failure and elevated intraocular pressure. Pharmaceutical compositions including these compounds and processes for their preparation are also provided.
- -
-
-
- Novel benzyl-3H-1,2,3,5-oxathiadiazole 2-oxides useful as antihyperglycemic agents
-
This invention relates to novel benzyl-3H-1,2,3,5-oxathiadiazole 2-oxides, to the processes for their preparation, to methods for using the compounds, and to pharmaceutical preparations thereof. The compounds have pharmaceutical properties which render th
- -
-
-