- Oxadiazole Derivatives as Dual Orexin Receptor Antagonists: Synthesis, Structure–Activity Relationships, and Sleep-Promoting Properties in Rats
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The orexin system plays an important role in the regulation of wakefulness. Suvorexant, a dual orexin receptor antagonist (DORA) is approved for the treatment of primary insomnia. Herein, we outline our optimization efforts toward a novel DORA. We started our investigation with rac-[3-(5-chloro-benzooxazol-2-ylamino)piperidin-1-yl]-(5-methyl-2-[1,2,3]triazol-2-ylphenyl)methanone (3), a structural hybrid of suvorexant and a piperidine-containing DORA. During the optimization, we resolved liabilities such as chemical instability, CYP3A4 inhibition, and low brain penetration potential. Furthermore, structural modification of the piperidine scaffold was essential to improve potency at the orexin 2 receptor. This work led to the identification of (5-methoxy-4-methyl-2-[1,2,3]triazol-2-ylphenyl)-{(S)-2-[5-(2-trifluoromethoxyphenyl)-[1,2,4]oxadiazol-3-yl]pyrrolidin-1-yl}methanone (51), a potent, brain-penetrating DORA with in vivo efficacy similar to that of suvorexant in rats.
- Brotschi, Christine,Roch, Catherine,Gatfield, John,Treiber, Alexander,Williams, Jodi T.,Sifferlen, Thierry,Heidmann, Bibia,Jenck, Francois,Bolli, Martin H.,Boss, Christoph
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supporting information
p. 1257 - 1270
(2019/06/17)
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- SUBSTITUTED 2,2'-BIPYRIMIDINYL COMPOUNDS, ANALOGUES THEREOF, AND METHODS USING SAME
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The present invention includes substituted 2,2'-bipyrimidinyl compounds, analogues thereof, and compositions comprising the same, which can be used to treat and/or prevent hepatitis B virus (HBV) and/or hepatitis B virus (HBV)-hepatitis D virus (HDV) infection in a patient.
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Page/Page column 112-113
(2019/12/04)
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- 2-(1,2,3-TRIAZOL-2-YL)BENZAMIDE AND 3-(1,2,3-TRIAZOL-2-YL)PICOLINAMIDE DERIVATIVES AS OREXIN RECEPTOR ANTAGONISTS
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The present invention relates to 2-(1,2,3-triazol-2-yl)benzamide and 3-(1,2,3-triazol-2-yl)picolinamide derivatives of formula (I) wherein Ar1, Q, and R1 to R5 are as described in the description, to their preparation, to
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Paragraph 0437; 0438
(2015/06/17)
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- ISOINDOLIN-1-ONES AS MACROPHAGE MIGRATION INHIBITORY FACTOR (MIF) INHIBITORS
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Compounds having an isoindolin-1-one backbone of Formula (I) are disclosed which have utility in treating and/or preventing microbial infections, tumor growth, metastasis and other macrophage migration inhibitory factor (MIF)-modulated pathological condit
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Paragraph 0368; 0369; 0370
(2015/07/02)
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- AZETIDINE AMIDE DERIVATIVES AS OREXIN RECEPTOR ANTAGONISTS
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The present invention relates to azetidine amide derivatives derivatives of formula (I) wherein rings A1 A2 and A3 are as described in the description, to pharmaceutically acceptable salts thereof, to their preparation, to
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Page/Page column 41; 42
(2014/09/29)
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- 2-(1,2,3-TRIAZOL-2-YL)BENZAMIDE AND 3-(1,2,3-TRIAZOL-2-YL)PICOLINAMIDE DERIVATIVES AS OREXIN RECEPTOR ANTAGONISTS
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The present invention relates to 2-(1,2,3-triazol-2-yl)benzamide and 3-(1,2,3-triazol-2- yl)picolinamide derivatives of formula (I) Formula (I) wherein Ar1, Q, and R1 to R5 are as described in the description, to their pre
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Page/Page column 59
(2013/05/23)
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- AMINO-ISO-INDOLE, AMINO-AZA-ISO-INDOLE, AMINO-DIHYDROISOQUINOLINE AND AMINO-BENZOXAZINE COMPOUNDS AS BETA-SECRETASE MODULATORS AND METHODS OF USE
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The present invention comprises a new class of compounds useful for the modulation of Beta-secretase enzyme activity and for the treatment of Beta-secretase mediated diseases, including Alzheimer?s disease (AD) and related conditions. In one embodiment, t
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- SPIRO-AMINO-IMIDAZO-FUSED HETEROCYCLIC COMPOUNDS AS BETA-SECRETASE MODULATORS AND METHODS OF USE
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The present invention provides a new class of compounds useful for the modulation of beta-secretase enzyme (BACE) activity. The compounds have a general Formula I, wherein variables A1, A3, A4, A5, A6, A8, R2, R7, X, Y and Z of Formula I are defined here
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- 5-AMINO-OXAZEPINE AND 5-AMINO-THIAZEPANE COMPOUNDS AS BETA-SECRETASE ANTAGONISTS AND METHODS OF USE
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The present invention provides a new class of compounds useful for the modulation of beta-secretase enzyme (BACE) activity. The compounds have a general Formula (I); wherein variables A1, A3, A4, A5, A6, As, R2, R7, X and Y of Formula (I) are defined here
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- SPIRO-AMINO-IMIDAZOLONE AND SPIRO-AMINO-DIHYDRO-PYRIMIDINONE COMPOUNDS AS BETA-SECRETASE MODULATORS AND METHODS OF USE
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The present invention provides a new class of compounds useful for the modulation of beta-secretase enzyme (BACE) activity. The compounds have a general Formula (I), wherein variables A1, A3, A4, A5, A6/su
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- SPIRO-TETRACYCLIC RING COMPOUNDS AS BETA - SECRETASE MODULATORS
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The present invention comprises a new class of compounds useful for the modulation of Beta-secretase enzyme activity and for the treatment of Beta-secretase mediated diseases, including Alzheimer's disease (AD) and other related conditions. In one embodiment, the compounds have a general Formula (I) wherein A1, A2, A3, A4, A5, A6, R2, R7, X and Y of Formula I are defined herein. The invention also includes use of these compounds in pharmaceutical compositions for treatment, prophylactic or therapeutic, of disorders and conditions related to the activity of beta-secretase protein. Such disorders include, for example, Alzheimer's Disease, cognitive deficits, cognitive impairment, schizophrenia and other central nervous system conditions related to and/or caused by the formation and/or deposition of plaque on the brain. The invention also comprises further embodiments of Formula I, intermediates and processes useful for the preparation of compounds of Formula I.
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- Synthesis of methyl-, fluoro-, and chloro-substituted 6-hydroxyisoindolin-1-ones
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The synthesis of a series of methyl-, fluoro-, and chloro-substituted 6-hydroxyisoindolin-1-ones is described.
- Powers, James J.,Favor, David A.,Rankin, Trent,Sharma, Rashmi,Pandit, Chetan,Jeganathan, Azhwarsamy,Maiti, Samarendra N.
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supporting information; experimental part
p. 1267 - 1269
(2009/09/05)
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- ISOINDOLE DERIVATIVES
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This invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, a process of making these compounds, pharmaceutical compositions containing one or more of these compounds or their salts, and their use for the treatment of schizophrenia, bipolar disorder, or other central nervous system disorders.
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Page/Page column 29
(2010/11/30)
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- Doxepin analogs and methods of use thereof
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The invention relates to novel antihistamines and methods of modulating sleep by administering a doxepin analog or a pharmaceutically effective salt thereof.
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Page/Page column 58; 59
(2008/06/13)
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