- An expeditious preparation of E-2-amino-5-hydroxyadamantane and its Z-isomer
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Reductive amination of 5-hydroxy-2-adamantanone with S-α-methylbenzylamine using 5% Rh-C as the catalyst in the presence of Al(iOPr)3 gave a 3:1 mixture of the E- and Z-5-hydroxy-adamantane-1-phenethylamines. Choice of catalyst, concentration,
- Jaroskova, Libuse,Van der Veken, Louis,de Belser, Paul,Diels, Gaston,de Groot, Alex,Linders, Joannes T.M.
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Read Online
- The development and SAR of pyrrolidine carboxamide 11β-HSD1 inhibitors
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The design and development of a series of highly selective pyrrolidine carboxamide 11β-HSD1 inhibitors are described. These compounds including PF-877423 demonstrated potent in vitro activity against both human and mouse 11β-HSD1 enzymes. In an in vivo assay, PF-877423 inhibited the conversion of cortisone to cortisol. Structure guided optimization effort yielded potent and stable 11β-HSD1 selective inhibitor 42.
- Cheng, Hengmiao,Hoffman, Jacqui,Le, Phuong,Nair, Sajiv K.,Cripps, Stephan,Matthews, Jean,Smith, Christopher,Yang, Michele,Kupchinsky, Stan,Dress, Klaus,Edwards, Martin,Cole, Bridget,Walters, Evan,Loh, Christine,Ermolieff, Jacques,Fanjul, Andrea,Bhat, Ganesh B.,Herrera, Jocelyn,Pauly, Tom,Hosea, Natilie,Paderes, Genevieve,Rejto, Paul
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Read Online
- Discovery and structural characterization of peficitinib (ASP015K) as a novel and potent JAK inhibitor
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Janus kinases (JAKs) are considered promising targets for the treatment of autoimmune diseases including rheumatoid arthritis (RA) due to their important role in multiple cytokine receptor signaling pathways. Recently, several JAK inhibitors have been developed for the treatment of RA. Here, we describe the identification of the novel orally bioavailable JAK inhibitor 18, peficitinib (also known as ASP015K), which showed moderate selectivity for JAK3 over JAK1, JAK2, and TYK2 in enzyme assays. Chemical modification at the C4-position of lead compound 5 led to a large increase in JAK inhibitory activity and metabolic stability in liver microsomes. Furthermore, we determined the crystal structures of JAK1, JAK2, JAK3, and TYK2 in a complex with peficitinib, and revealed that the 1H-pyrrolo[2,3–b]pyridine-5-carboxamide scaffold of peficitinib forms triple hydrogen bonds with the hinge region. Interestingly, the binding modes of peficitinib in the ATP-binding pockets differed among JAK1, JAK2, JAK3, and TYK2. WaterMap analysis of the crystal structures suggests that unfavorable water molecules are the likely reason for the difference in orientation of the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold to the hinge region among JAKs.
- Hamaguchi, Hisao,Amano, Yasushi,Moritomo, Ayako,Shirakami, Shohei,Nakajima, Yutaka,Nakai, Kazuo,Nomura, Naoko,Ito, Misato,Higashi, Yasuyuki,Inoue, Takayuki
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p. 4971 - 4983
(2018/08/29)
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- Discovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells
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A collaborative high throughput screen of 1.35 million compounds against mutant (R132H) isocitrate dehydrogenase IDH1 led to the identification of a novel series of inhibitors. Elucidation of the bound ligand crystal structure showed that the inhibitors exhibited a novel binding mode in a previously identified allosteric site of IDH1 (R132H). This information guided the optimization of the series yielding submicromolar enzyme inhibitors with promising cellular activity. Encouragingly, one compound from this series was found to induce myeloid differentiation in primary human IDH1 R132H AML cells in vitro.
- Jones, Stuart,Ahmet, Jonathan,Ayton, Kelly,Ball, Matthew,Cockerill, Mark,Fairweather, Emma,Hamilton, Nicola,Harper, Paul,Hitchin, James,Jordan, Allan,Levy, Colin,Lopez, Ruth,McKenzie, Eddie,Packer, Martin,Plant, Darren,Simpson, Iain,Simpson, Peter,Sinclair, Ian,Somervaille, Tim C.P.,Small, Helen,Spencer, Gary J.,Thomson, Graeme,Tonge, Michael,Waddell, Ian,Walsh, Jarrod,Waszkowycz, Bohdan,Wigglesworth, Mark,Wiseman, Daniel H.,Ogilvie, Donald
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supporting information
p. 11120 - 11137
(2016/12/30)
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- Adamantyl analogues of paracetamol as potent analgesic drugs via inhibition of TRPA1
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Paracetamol also known as acetaminophen, is a widely used analgesic and antipyretic agent. We report the synthesis and biological evaluation of adamantyl analogues of paracetamol with important analgesic properties. The mechanism of nociception of compoun
- Fresno, Nieves,Prez-Fernndez, Ruth,Goicoechea, Carlos,Alkorta, Ibon,Fernndez-Carvajal, Asia,De La Torre-Martnez, Roberto,Quirce, Susana,Ferrer-Montiel, Antonio,Martn, M. Isabel,Goya, Pilar,Elguero, Jos
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- Optimization of brain penetrant 11β-hydroxysteroid dehydrogenase type i inhibitors and in vivo testing in diet-induced obese mice
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11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been widely considered by the pharmaceutical industry as a target to treat metabolic syndrome in type II diabetics. We hypothesized that central nervous system (CNS) penetration might be required to see efficacy. Starting from a previously reported pyrimidine compound, we removed hydrogen-bond donors to yield 3, which had modest CNS penetration. More significant progress was achieved by changing the core to give 40, which combines good potency and CNS penetration. Compound 40 was dosed to diet-induced obese (DIO) mice and gave excellent target engagement in the liver and high free exposures of drug, both peripherally and in the CNS. However, no body weight reduction or effects on glucose or insulin were observed in this model. Similar data were obtained with a structurally diverse thiazole compound 51. This work casts doubt on the hypothesis that localized tissue modulation of 11β-HSD1 activity alleviates metabolic syndrome.
- Goldberg, Frederick W.,Dossetter, Alexander G.,Scott, James S.,Robb, Graeme R.,Boyd, Scott,Groombridge, Sam D.,Kemmitt, Paul D.,Sj?gren, Tove,Gutierrez, Pablo Morentin,Deschoolmeester, Joanne,Swales, John G.,Turnbull, Andrew V.,Wild, Martin J.
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supporting information
p. 970 - 986
(2014/03/21)
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- 2, 4 -DIAMINOPYRIMIDINE DERIVATIVES AS PROTEIN KINASE INHIBITORS
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The present invention relates to novel pyrimide derivatives of formula (I): that are useful as kinase inhibitors. More particularly, the present invention relates to novel pyrimidine compounds, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of proliferative disorders.
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Page/Page column 68-69
(2012/05/20)
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- Imidazopyridine derivatives as JAK inhibitors
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New imidazopyridine derivatives having the chemical structure of formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Janus Kinases (JAK).
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Paragraph 0219; 0220
(2013/03/26)
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- INHIBITORS OF 11BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1
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This invention relates to novel compounds of the Formula (I*), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof which are useful for the therapeutic treatment of diseases associated with the modulation or inhibition of 11
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Page/Page column 36
(2011/02/26)
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- COMPOUND HAVING 11 ?-HSD1 INHIBITORY ACTIVITY
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The present invention provides compounds having excellent 11β-HSD1 inhibitory activity. A compound represented by the following formula (I): [wherein X1 represents an oxygen atom, or the formula -(CR11R12)p-, etc., Y1 represents a hydrogen atom, a hydroxyl group, etc., Z1 represents an oxygen atom or the formula -(NR14)-, R1 represents a hydrogen atom, a halogen atom, a cyano group, a C1-4 alkyl group, a C1-4 alkyl group substituted with 1 to 3 halogen atoms, a C1-4 alkoxy group, a C1-4 alkoxycarbonyl group, a carboxyl group, a carbamoyl group, or an amino group, and m represents an integer of 1 or 2, and R2 represents a hydrogen atom or a C1-4 alkyl group, and n represents an integer of 1 or 2].
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Page/Page column 9
(2010/04/25)
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- ADAMANTYL BENZAMIDE COMPOUNDS
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Embodiments of the present invention provide adamantyl benzamide derivtives and pharmaceutical compositions comprising adamantyl benzamide derivatives. Methods of use of such compounds and compositions to modulate the activity of 11β-hydroxysteroid dehydr
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Page/Page column 35-36
(2010/07/10)
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- Selective hydroxylation of adamantane and its derivatives
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A general method was developed for hydroxylation into the nodal position of adamantane and its 1- and 2-substituted derivatives employing systems H 2O-CBr4 (BrCCl3, CCl4) in the presence of complexes of Pd, Ni, Ru, Co, Mo, W, and Fe. The oxidants in the systems are hypochlorous (HOCl) or hypobromous (HOBr) acids generated from water and halomethanes under the reaction conditions.
- Khusnutdinov,Shchadneva,Mukhametshina,Dzhemilev
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scheme or table
p. 1137 - 1142
(2009/12/03)
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- PROCESS FOR PRODUCTION OF HYDROXYADAMANTANEAMINE
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Disclosed is a process for producing 1-hydroxy-4-aminoadamantane.
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(2009/09/05)
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- N-ADAMANTYL BENZAMIDES AS INHIBITORS OF 11-BETA-HYDROXYSTEROID DEHYDROGENASE
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Novel substituted benzamide based inhibitors, their use in therapy, pharmaceutical compositions comprising the compounds, the use of said compounds in the manufacture of medicaments, and therapeutic methods comprising the administration of said compounds
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Page/Page column 56
(2008/12/08)
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- NOVEL COMPOUNDS
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Novel substituted benzamide based inhibitors, their use in therapy, pharmaceutical compositions comprising the compounds, the use of said compounds in the manufacture of medicaments, and therapeutic methods comprising the administration of said compounds are described. The present compounds modulate the activity of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and are accordingly useful in the treatment of diseases in which such a modulation is beneficial, such as the metabolic syndrome.
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Page/Page column 67
(2008/12/08)
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- NEW IMIDAZOLONE AND IMIDAZOLIDINONE DERIVATIVES AS 11B-HSD1 INHIBITORS
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Compounds of formula as well as pharmaceutically acceptable salts and esters thereof, wherein R1 to R6 have the significance given in claim 1 can be used in the form of pharmaceutical compositions.
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Page/Page column 31
(2008/06/13)
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- Discovery and metabolic stabilization of potent and selective 2-amino-N-(adamant-2-yl) acetamide 11β-hydroxysteroid dehydrogenase type 1 inhibitors
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Starting from a rapidly metabolized adamantane 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor 22a, a series of E-5-hydroxy-2-adamantamine inhibitors, exemplified by 22d and (±)-22f, was discovered. Many of these compounds are potent inhibitors of 11β-HSD1 and are selective over 11β-HSD2 for multiple species (human, mouse, and rat), unlike other reported species-selective series. These compounds have good cellular potency and improved microsomal stability. Pharmacokinetic profiling in rodents indicated moderate to large volumes of distribution, short half-lives, and a pharmacokinetic species difference with the greatest exposure measured in rat with 22d. One hour postdose liver, adipose, and brain tissue 11β-HSD1 inhibition was confirmed with (±)-22f in a murine ex vivo assay. Although 5,7-disubstitued-2-adamantamines provided greater stability, a single, E-5-position, polar functional group afforded inhibitors with the best combination of stability, potency, and selectivity. These results indicate that adamantane metabolic stabilization sufficient to obtain short-acting, potent, and selective 11β-HSD1 inhibitors has been discovered.
- Rohde, Jeffrey J.,Pliushchev, Marina A.,Sorensen, Bryan K.,Wodka, Dariusz,Shuai, Qi,Wang, Jiahong,Fung, Steven,Monzon, Katina M.,Chiou, William J.,Pan, Liping,Deng, Xiaoqing,Chovan, Linda E.,Ramaiya, Atul,Mullally, Mark,Henry, Rodger F.,Stolarik, DeAnne F.,Imade, Hovis M.,Marsh, Kennan C.,Beno, David W. A.,Fey, Thomas A.,Droz, Brian A.,Brune, Michael E.,Camp, Heidi S.,Sham, Hing L.,Frevert, Ernst Uli,Jacobson, Peer B.,Link
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p. 149 - 164
(2008/02/01)
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- Discovery of adamantane ethers as inhibitors of 11β-HSD-1: Synthesis and biological evaluation
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A novel class of adamantane ethers 11β-hydroxysteroid hydrogenase type I inhibitors has been discovered. These compounds have excellent HSD-1 potency and selectivity against HSD-2. The structure-activity relationships, selectivity, metabolism, PK, ex vivo
- Patel, Jyoti R.,Shuai, Qi,Dinges, Jurgen,Winn, Marty,Pliushchev, Marina,Fung, Steven,Monzon, Katina,Chiou, William,Wang, Jiahong,Pan, Liping,Wagaw, Seble,Engstrom, Kenneth,Kerdesky, Francis A.,Longenecker, Kenton,Judge, Russell,Qin, Wenying,Imade, Hovis M.,Stolarik, DeAnne,Beno, David W.A.,Brune, Michael,Chovan, Linda E.,Sham, Hing L.,Jacobson, Peer,Link
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p. 750 - 755
(2007/10/03)
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- Adamantyl-pyrazole carboxamides as inhibitors of 11B-hydroxysteroid dehydrogenase
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Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of diseases such as, for example, type II diabetes mellitus and metabolic syndrome.
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Page/Page column 16
(2008/06/13)
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- Thiazoles as inhibitors of 11B-hydroxysteroid dehydrogenase
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Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of diseases such as, for example, type II diabetes mellitus and metabolic syndrome.
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Page/Page column 11
(2008/06/13)
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- 2-Adamantylurea derivatives as selective 11B-HSD1 inhibitors
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The present invention relates to 2-adamantylurea derivatives of formula I as selective inhibitors of the enzyme 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and the use of such compounds for the treatment and prevention of metabolic syndrome, di
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Page/Page column 22
(2008/06/13)
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- Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
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The present invention relates to compounds which are inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme. The present invention further relates to the use of inhibitors of 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme for the treatme
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Page/Page column 40
(2010/02/14)
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- Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
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The present invention relates to compounds which are inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme. The present invention further relates to the use of inhibitors of 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme for the treatment of non-insulin dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome, and other diseases and conditions that are mediated by excessive glucocorticoid action.
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(2008/06/13)
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- Hyperconjugative control by remote substituents of diastereoselectivity in the oxygenation of hydrocarbons
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(figure presented) The oxidation of 2-substituted adamantanes (2) with TFDO (1) is reported. The data show a stereodifferentiation of the chemical environments induced by remote electron-withdrawing substituents which produces remarkable Z/E diastereosele
- Gonzalez-Nunez, Maria E.,Royo, Jorge,Castellano, Gloria,Andreu, Cecilia,Boix, Carmen,Mello, Rossella,Asensio, Gregorio
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p. 831 - 834
(2007/10/03)
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- AMINO BI- AND TRI-CARBOCYCLIC AKLANE BIS-ARYL SQUALENE SYNTHASE INHIBITORS
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This invention relates to a class of novel amino bi- and tri-carbocyclic alkane compounds having bis-aryl substitution which exhibit squalene synthase inhibition properties. The bi- and tri-carbocyclic alkane ring contains an amino group and the ring is further linked or bridged to two mono- and/or bicyclic rings. Compounds of this invention reduce levels of serum cholesterol in the body without significantly reducing mevalonic metabolite synthesis. This invention relates also to pharmacological compositions and method of treatment for lowering serum cholesterol levels using the compounds of this invention.
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