- Lead evaluation of tetrahydroquinolines as nonsteroidal selective androgen receptor modulators for the treatment of osteoporosis
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Tetrahydroquinoline (THQ) was deemed to be a suitable scaffold for our nonsteroidal selective androgen receptor modulator (SARM) concept. We adapted the strategy of switching the antagonist function of cyano-group-containing THQ (CN-THQ) to the agonist function and optimized CN-THQ as an orally available drug candidate with suitable pharmacological and ADME profiles. Based on binding mode analyses and synthetic accessibility, we designed and synthesized a compound that possesses a para-substituted aromatic ring attached through an amide linker. The long-tail THQ derivative 6-acetamido-N-(2-(8-cyano-3a,4,5,9b- tetrahydro-3H-cyclopenta[c]quinolin-4-yl)-2-methylpropyl)nicotinamide (1 d), which bears a para-acetamide-substituted aromatic group, showed an appropriate in vitro biological profile, as expected. We considered that the large conformational change at Trp741 of the androgen receptor (AR) and the hydrogen bond between 1 d and helix 12 of the AR could maintain the structure of the AR in its agonist form; indeed, 1 d displays strong AR agonistic activity. Furthermore, 1 d showed an appropriate in vivo profile for use as an orally available SARM, displaying clear tissue selectivity, with a separation between its desirable osteoanabolic effect on femoral bone mineral density and its undesirable virilizing effects on the uterus and clitoral gland in a female osteoporosis model. Long-tail THQ as a SARM: We describe the lead evaluation process of tetrahydroquinolines (THQs) as nonsteroidal selective androgen receptor modulators (SARMs). The strategy of switching from AR antagonist to AR agonist was successfully applied to CN-THQ, and we identified a long-tail THQ as a novel SARM. This new THQ showed a certain degree of tissue selectivity, with a separation between its desirable osteoanabolic effect and its undesirable virilizing effects in a female osteoporosis model. Copyright
- Nagata, Naoya,Furuya, Kazuyuki,Oguro, Nao,Nishiyama, Daisuke,Kawai, Kentaro,Yamamoto, Noriko,Ohyabu, Yuki,Satsukawa, Masahiro,Miyakawa, Motonori
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Read Online
- NOVEL COMPOUNDS FOR THE TREATMENT OF PARASITIC INFECTIONS
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The present invention relates to novel compounds or pharmaceutically acceptable salts thereof, corresponding compositions, and methods and/or uses in therapy, for example in the treatment of parasitic infections such as malaria, in particular infection by
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Page/Page column 41
(2019/08/14)
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- 3-OXO-1,4-DIAZEPINYLE COMPOUNDS AS NRF2 ACTIVATORS
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The present invention relates to bisaryl lactam compounds, methods of making them, pharmaceutical compositions containing them and their use as NRF2 activators. In particular, the compounds of this invention include a compound of Formula (I):
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Page/Page column 52; 56
(2018/07/05)
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- Novel benzoxazolone compound
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PROBLEM TO BE SOLVED: To provide a therapeutic agent for diseases such as neuropathic pain, nociceptive pain, inflammatory pain, small diameter fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria or multiple sclerosis. SOLUTION: There is provided a benzoxazolone compound represented by the formula (1) or a pharmaceutically acceptable salt. (1), where R1 and R2 are each independently H or C1-6 alkyl, where the alkyl may be substituted by hydroxy, C1-4 alkylsulfonyl, aminocarbonyl or 4 to 7-membered heterocycloalkyl, or the like, L is C1-6 alkylene, R3 is C1-6 alkyl, C3-7 cycloalkyl, where the cycloalkyl may be substituted by halogen or hydroxy or the like, C6-10 aryl, where the aryl may be substituted by halogen, C1-4 alkyl or C1-4 haloalkyl or the like, R4 is H, halogen or C1-4 alkyl. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT
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Paragraph 0206 - 0208
(2017/04/27)
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- LSD1 INHIBITORS AND USES THEREOF
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Provided are novel compounds of Formula (I) and pharmaceutically acceptable salts thereof, which are useful for treating a variety of diseases, disorders or conditions, associated with LSDl. Also provided are pharmaceutical compositions comprising the novel compounds of Formula (I), pharmaceutically acceptable salts thereof, and methods for their use in treating one or more diseases, disorders or conditions, associated with LSDl.
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Paragraph 00797-00798
(2016/11/17)
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- HETEROCYCLIC DERIVATIVE AS MICROSOMAL PROSTAGLANDIN E SYNTHASE (mPGEs) INHIBITOR
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The present invention provides a novel heterocyclic derivative or a pharmaceutically acceptable salt thereof. For example, the present invention provides a heterocyclic derivative of the general formula [1] or its tautomer, or a pharmaceutically acceptable salt thereof: wherein R 1 and R 2 are same or diferent aromatic ring, etc., and ring A is a heterocyclic ring. The compound of the invention or a pharmaceutically acceptable salt thereof has potent mPGES-1 inhibiting activity and is useful as an agent for the treatment or prevension of a disease, such as rheumatoid arthritis, osteoarthritis, temporomandibular joint disorders, low back pain, endometriosis, dysmenorrhea, overactive bladder, malignant tumors or neurodegenerative disease.
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Paragraph 0097
(2015/12/04)
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- TRICYCLIC COMPOUNDS FOR USE AS KINASE INHIBITORS
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There is provided compounds of formula (I), wherein R1, R2, X, R3 and R4 have meanings given in the description (and which compounds are optionally substituted as indicated in the description), and pharmaceutically-acceptable esters, amides, solvates or salts thereof, which compounds are useful in the treatment of diseases in which inhibition of a protein or lipid kinase (e.g. a PIM family kinase, such as PIM-1, PIM-2 and/or PIM-3) is desired and/or required, and particularly in the treatment of cancer or a proliferative disease. There is also provided combinations comprising the compounds of formula (I).
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Page/Page column 67
(2013/03/26)
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- HETEROCYCLIC COMPOUNDS CONTAINING A PYRROLOPYRIDINE OR BENZIMIDAZOLE CORE
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The present invention relates to compounds of Formula (I) and pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5 and n are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.
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Page/Page column 53
(2011/06/26)
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- HETEROCYCLIC COMPOUNDS CONTAINING AN INDOLE CORE
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Disclosed are novel compounds which inhibit RSK, methods of making such compounds and pharmaceutical compositions comprising such compounds. Also disclosed are methods of treating RSK2 regulated disorders using compounds of the invention.
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Page/Page column 71
(2011/06/26)
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- HETEROCYCLIC COMPOUND
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The present invention provides to a compound having melanin-concentrating hormone receptor antagonistic action and low toxicity, and useful as a agent for the prophylaxis or treatment of obesity and the like. The present invention relates to a compound re
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Page/Page column 43-44
(2010/12/30)
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- EXTERNALLY MASKED NEOPENTYL SULFONYL ESTER CYCLIZATION RELEASE PRODRUGS OF ACAMPROSATE, COMPOSITIONS THEREOF, AND METHODS OF USE
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Masked nitrogen-substituted and oxygen-substituted neopentyl sulfonyl ester prodrugs of acamprosate, pharmaceutical compositions comprising such prodrugs, and methods of using such prodrugs and compositions thereof for treating diseases are disclosed. In particular, acamprosate prodrugs exhibiting enhanced oral bioavailability and methods of using acamprosate prodrugs to treat neurodegenerative disorders, psychotic disorders, mood disorders, anxiety disorders, somatoform disorders, movement disorders, substance abuse disorders, binge eating disorder, cortical spreading depression related disorders, tinnitus, sleeping disorders, multiple sclerosis, and pain are disclosed.
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Page/Page column 39
(2009/04/24)
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- ANTITHROMBOTIC DIAMIDES
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This application relates to a compound of formula (I) (or a pharmaceutically acceptable salt of the compound) as defined herein, pharmaceutical compositions thereof, and its use as an inhibitor of factor Xa and/or thrombin, as well as a process for its preparation and intermediates therefor.
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Page/Page column 72
(2008/06/13)
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- Heterocyclic inhibitors of MEK and methods of use thereof
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Disclosed are compounds of the Formula I and pharmaceutically acceptable salts and prodrugs thereof, wherein R1, R2, R7, R8, R9 and R10, W and Y are as defined in the specification. Such compounds are MEK inhibitors and useful in the treatment of hyperproliferative diseases, such as cancer and inflammation, in mammals. Also disclosed are methods of using such compounds in the treatment of hyperproliferative diseases in mammals and pharmaceutical compositions containing such compounds.
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- PYRAZOLE DERIVATIVES, MEDICINAL COMPOSITION CONTAINING THE SAME, MEDICINAL USE THEREOF, AND INTERMEDIATE FOR PRODUCTION THEREOF
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The present invention provides pyrazole derivatives represented by the general formula: wherein R1 represents H, an optionally substituted C1-6 alkyl group etc.; one of Q and T represents a group represented by the general formula: or a group represented by the general formula: while the other represents an optionally substituted C1-6 alkyl group etc.; R2 represents H, a halogen atom, OH, an optionally substituted C1-6 alkyl group etc.; X represents a single bond, O or S; Y represents an optionally substituted C1-6 alkylene group etc.; Z represents -RB, -CORC etc. in which RB represents an optionally substituted C1-6 alkyl group etc.; and RC represents an optionally substituted C1-6 alkyl group etc.,; R4 represents H, an optionally substituted C1-6 alkyl group etc.; and R3, R5 and R6 represent H, a halogen atom etc., pharmaceutically acceptable salts thereof or prodrugs thereof, which exhibit an excellent inhibitory activity in human SGLT1 and are useful as agents for the prevention or treatment of a disease associated with hyperglycemia such as diabetes, impaired glucose tolerance, impaired fasting glycemia, diabetic complications or obesity, and a disease associated with the increase of blood galactose level such as galactosemia, and pharmaceutical compositions comprising the same, pharmaceutical uses thereof, and intermediates for production thereof.
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Page/Page column 89-90
(2010/02/12)
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- CHK-1 INHIBITORS
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Disclosed are novel inhibitors of Chk-1 and methods of using the same for therapy.
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Page/Page column 209
(2010/02/11)
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- ANTITHROMBOTIC ETHERS
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This application relates to a compound of formula I (or a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug thereof) as defined herein, pharmaceutical compositions thereof, and its use as an inhibitor of factor Xa and/or thrombin, as well as a process for its preparation and intermediates therefor (I).
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- N-silyl-tethered radical cyclizations: a new synthesis of gamma-amino alcohols.
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[reaction: see text] Various allylic and propargylic amines bearing a protecting group (PG) have been employed in N-silyl-tethered radical cyclizations. The resulting silapyrrolidine adducts could be smoothly oxidized, creating access to gamma-amino alcoh
- Blaszykowski, Christophe,Dhimane, Anne-Lise,Fensterbank, Louis,Malacria, Max
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p. 1341 - 1344
(2007/10/03)
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