- Discovery and synthesis of tetrahydropyrimidinedione-4-carboxamides as endothelial lipase inhibitors
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Endothelial lipase (EL) inhibitors have been shown to elevate HDL-C levels in pre-clinical murine models and have potential benefit in prevention and treatment of cardiovascular diseases. Modification of the 1-ethyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (DHP) lead, 1, led to the discovery of a series of potent tetrahydropyrimidinedione (THP) EL inhibitors. Synthesis and SAR studies including modification of the amide group, together with changes on the pyrimidinone core led to a series of arylcycloalkyl, indanyl, and tetralinyl substituted 5-amino or 5-hydroxypyrimidinedione-4-carboxamides. Several compounds were advanced to PK evaluation. Among them, compound 4a was one of the most potent with measurable ELHDL hSerum potency and compound 3g demonstrated the best overall pharmacokinetic parameters.
- Hu, Carol H.,Wang, Tammy C.,Qiao, Jennifer X.,Haque, Lauren,Chen, Alice Y.A.,Taylor, David S.,Ying, Xiaohong,Onorato, Joelle M.,Galella, Michael,Shen, Hong,Huang, Christine S.,Toussaint, Nathalie,Li, Yi-Xin,Abell, Lynn,Adam, Leonard P.,Gordon, David,Wexler, Ruth R.,Finlay, Heather J.
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Read Online
- Stereospecificity in Intramolecular Photoredox Reactions of Naphthoquinones: Enantioselective Total Synthesis of (?)-Spiroxin C
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Intramolecular photoredox reactions of naphthoquinone derivatives were found to proceed in a stereospecific manner. This method was used as a basis for the enantioselective total synthesis of (?)-spiroxin C.
- Ando, Yoshio,Hanaki, Atsuko,Sasaki, Ryota,Ohmori, Ken,Suzuki, Keisuke
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- The evaluation of 1-tetralone and 4-chromanone derivatives as inhibitors of monoamine oxidase
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Abstract: Monoamine oxidase (MAO) is of much clinical relevance, and inhibitors of this enzyme are used in the treatment for neuropsychiatric and neurodegenerative disorders such as depression and Parkinson’s disease. The present study synthesises and evaluates the MAO inhibition properties of a series of 33 1-tetralone and 4-chromanone derivatives in an attempt to discover high-potency compounds and to expand on the structure–activity relationships of MAO inhibition by these classes. Among these series, eight submicromolar MAO-A inhibitors and 28 submicromolar MAO-B inhibitors are reported, with all compounds acting as specific inhibitors of the MAO-B isoform. The most potent inhibitor was a 1-tetralone derivative (1h) with IC50 values of 0.036 and 0.0011?μM for MAO-A and MAO-B, respectively. Interestingly, with the reduction of 1-tetralones to the corresponding alcohols, a decrease in MAO inhibition potency is observed. Among these 1-tetralol derivatives, 1p (IC50 = 0.785?μM) and 1o (IC50 = 0.0075?μM) were identified as particularly potent inhibitors of MAO-A and MAO-B, respectively. Potent compounds such as those reported here may act as leads for the future development of MAO-B specific inhibitors. Graphic abstract: The present study describes the MAO inhibitory activities of a series of 1-tetralone and 4-chromanone derivatives. Numerous high-potency MAO-B specific inhibitors were identified.[Figure not available: see fulltext.].
- Cloete, Stephanus J.,N’Da, Clarina I.,Legoabe, Lesetja J.,Petzer, Anél,Petzer, Jacobus P.
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p. 491 - 507
(2020/10/02)
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- TETRAHYDRONAPHTHALENE DERIVATIVE
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A compound shown by general formula (I-1) (in the formula, all symbols are as stated in the specification.) has selective S1P5 receptor-binding activity. Adjusting this activity make s it possible to obtain a therapeutic agent for S1P5-mediated diseases,
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Paragraph 0144
(2018/12/13)
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- Practical synthesis of PGI2 agonist: Resolution-inversion- recycle approach of its chiral intermediate
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Practical synthesis of ((2R)-5-benzyloxy-2-hydroxy-1,2,3,4- tetrahydronaphth-2-yl)methanol ((R)-7b), a key chiral intermediate for the synthesis of the novel PGI2 agonist, (R)-[6-[(diphenylcarbamoyloxy) methyl]-6-hydroxy-5,6,7,8-tetrahydronapht
- Ohigashi, Atsushi,Kanda, Atsushi,Moriki, Shigeru,Baba, Yukihisa,Hashimoto, Norio,Okada, Minoru
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p. 658 - 665
(2013/07/05)
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- The discovery of tertiary-amine LXR agonists with potent cholesterol efflux activity in macrophages
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The liver X receptors (LXR) play a key role in cholesterol homeostasis and lipid metabolism. SAR studies around tertiary-amine lead molecule 2, an LXR full agonist, revealed that steric and conformational changes to the acetic acid and propanolamine groups produce dramatic effects on agonist efficacy and potency. The new analogs possess good functional activity, demonstrating the ability to upregulate LXR target genes, as well as promote cholesterol efflux in macrophages.
- Marino Jr., Joseph P.,Kallander, Lara S.,Ma, Chun,Oh, Hye-Ja,Lee, Dennis,Gaitanopoulos, Dimitri E.,Krawiec, John A.,Parks, Derek J.,Webb, Christine L.,Ziegler, Kelly,Jaye, Michael,Thompson, Scott K.
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scheme or table
p. 5617 - 5621
(2010/04/30)
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- 4,5-DIHYDRONAPHTHO [1,2-b] THIOPHENE DERIVATIVE
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A 4,5-dihydronaphtho[1,2-b]thiophene derivative expressed by the formula: (wherein R1 is a C1 to C10 1-hydroxyalkyl group or a C1 to C10 acyl group, and R2 and R3 separately substitute in the 6-, 7-, 8-, or 9-positions, and are each independently a hydrogen atom, a halogen atom, a C1 to C10 alkyl group, a hydroxy group, a C1 to C10 alkoxy group, a C1 to C5 alkenyloxy group, a C1 to C5 alkynyloxy group, a benzyloxy group, or the like, provided that when R1 is an acyl group and R2 is a hydrogen atom, then R3 is neither a hydrogen atom nor an acetyl group), or a pharmaceutically acceptable salt thereof. This is a novel compound that is effective in reducing triglyceride levels in the liver and reducing blood glucose levels.
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Page/Page column 16
(2010/11/08)
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- COMPOUNDS AND METHODS
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Disclosed are compounds and pharmaceutically acceptable salts thereof, useful as LXR agonists.
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Page/Page column 32
(2008/06/13)
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- A new chiral oxathiane: Synthesis, resolution and absolute configuration determination by vibrational circular dichroism
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A new oxathiane, derived from 5-hydroxy-1-tetralone has been synthesized in eight steps, fully characterized as cis-fused rings by 1D and 2D NMR and resolved by preparative chiral chomatography (CHIRALCEL OD-R). The second eluting (+, MeOH)-isomer was ass
- Solladie-Cavallo,Balaz,Salisova,Suteu,Nafie,Cao,Freedman
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p. 2605 - 2611
(2007/10/03)
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- Medetomidine analogs as α2-adrenergic ligands. 3. Synthesis and biological evaluation of a new series of medetomidine analogs and their potential binding interactions with α2-adrenoceptors involving a 'methyl pocket'
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The synthesis and the biological evaluation of a new series of medetomidine analogs are reported. The substitution pattern at the phenyl ring of the tetralin analogs had a distinct influence on the α2- adrenoceptor binding affinity. 4-Methylindan analog 6 was the most potent α2-adrenoceptor binding ligand among these 4-substituted imidazoles, and its α2-adrenoceptor selectivity was greater than the 5-methyl tetralin analog 4c. Ligand-pharmacophore and receptor modeling were combined to rationalize α2-adrenoceptor binding data of the imidazole analogs in terms of ligand-receptor interactions. The structure-activity relationships that were apparent from this and previous studies were qualitatively rationalized by the binding site models of the α2-adrenoceptor. The benzylic methyl group of medetomidine or the naphthyl analog 2a was superimposable with the α-methyl group of (-)-α-methylnorepinephrine and fit into the proposed 'methyl pocket' of the α2-adrenoceptor defined by the residues Leu110, Leu169, Phe391, and Thr395.
- Zhang, Xiaoyan,De Los Angeles, Joseph E.,He, Mei-Ying,Dalton, James T.,Shams, Gamal,Lei, Longping,Patil, Popat N.,Feller, Dennis R.,Miller, Duane D.,Hsu, Fu-Lian
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p. 3014 - 3024
(2007/10/03)
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