- Structure-Kinetic Profiling of Haloperidol Analogues at the Human Dopamine D2 Receptor
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Haloperidol is a typical antipsychotic drug (APD) associated with an increased risk of extrapyramidal side effects (EPSs) and hyperprolactinemia relative to atypical APDs such as clozapine. Both drugs are dopamine D2 receptor (D2R) antagonists, with contrasting kinetic profiles. Haloperidol displays fast association/slow dissociation at the D2R, whereas clozapine exhibits relatively slow association/fast dissociation. Recently, we have provided evidence that slow dissociation from the D2R predicts hyperprolactinemia, whereas fast association predicts EPS. Unfortunately, clozapine can cause severe side effects independent of its D2R action. Our results suggest an optimal kinetic profile for D2R antagonist APDs that avoids EPS. To begin exploring this hypothesis, we conducted a structure-kinetic relationship study of haloperidol and revealed that subtle structural modifications dramatically change binding kinetic rate constants, affording compounds with a clozapine-like kinetic profile. Thus, optimization of these kinetic parameters may allow development of novel APDs based on the haloperidol scaffold with improved side-effect profiles.
- Fyfe, Tim J.,Kellam, Barrie,Sykes, David A.,Capuano, Ben,Scammells, Peter J.,Lane, J. Robert,Charlton, Steven J.,Mistry, Shailesh N.
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p. 9488 - 9520
(2019/11/11)
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- Light-Mediated Formal Radical Deoxyfluorination of Tertiary Alcohols through Selective Single-Electron Oxidation with TEDA2+.
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The synthesis of tertiary alkyl fluorides through a formal radical deoxyfluorination process is described herein. This light-mediated, catalyst-free methodology is fast and broadly applicable allowing for the preparation of C?F bonds from (hetero)benzylic, propargylic, and non-activated tertiary alcohol derivatives. Preliminary mechanistic studies support that the key step of the reaction is the single-electron oxidation of cesium oxalates—which are readily available from the corresponding tertiary alcohols—with in situ generated TEDA2+. (TEDA: N-(chloromethyl)triethylenediamine), a radical cation derived from Selectfluor.
- Aguilar Troyano, Francisco José,Ballaschk, Frederic,Jaschinski, Marcel,?zkaya, Yasemin,Gómez-Suárez, Adrián
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supporting information
p. 14054 - 14058
(2019/11/11)
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- Monoamine Oxidase (MAO-N) Whole Cell Biocatalyzed Aromatization of 1,2,5,6-Tetrahydropyridines into Pyridines
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A sustainable MAO-N biocatalyzed process for the synthesis of pyridines from aliphatic tetrahydropyridines (THP) has been developed. Pyridine compounds were synthesized under mild reaction conditions and with high conversion, exploiting MAO-N whole cells as aromatizing biocatalysts. The kinetic profile of the whole cell biocatalytic transformation was finally investigated via in situ 19F NMR.
- Toscani, Anita,Risi, Caterina,Black, Gary W.,Brown, Nicola L.,Shaaban, Ali,Turner, Nicholas J.,Castagnolo, Daniele
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p. 8781 - 8787
(2018/09/06)
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- A Versatile Route to Unstable Diazo Compounds via Oxadiazolines and their Use in Aryl–Alkyl Cross-Coupling Reactions
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Coupling of readily available boronic acids and diazo compounds has emerged recently as a powerful metal-free carbon–carbon bond forming method. However, the difficulty in forming the unstable diazo compound partner in a mild fashion has hitherto limited their general use and the scope of the transformation. Here, we report the application of oxadiazolines as precursors for the generation of an unstable family of diazo compounds using flow UV photolysis and their first use in divergent protodeboronative and oxidative C(sp2)?C(sp3) cross-coupling processes, with excellent functional-group tolerance.
- Greb, Andreas,Poh, Jian-Siang,Greed, Stephanie,Battilocchio, Claudio,Pasau, Patrick,Blakemore, David C.,Ley, Steven V.
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p. 16602 - 16605
(2017/12/13)
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- METALLO-BETA-LACTAMASE INHIBITORS
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The present invention relates to compounds of formula (I) that are metallo-β-lactamase inhibitors, the synthesis of such compounds, and the use of such compounds for use with β-lactam antibiotics for overcoming resistance.
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Paragraph 0794
(2016/12/01)
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- METALLO-BETA-LACTAMASE INHIBITORS
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The present invention relates to compounds of formula (I) that are metallo-β-lactamase inhibitors, the synthesis of such compounds, and the use of such compounds for use with β-lactam antibiotics for overcoming resistance.
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Page/Page column 220
(2015/08/06)
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- HETEROCYCLIC MODULATORS OF LIPID SYNTHESIS AND COMBINATIONS THEREOF
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Heterocyclic modulators of lipid synthesis are provided as well as pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such compounds; and methods of treating conditions characterized by disregulation of a fatty acid synthase pathway by the administration of such compounds and combinations of such compounds and other therapeutic agents.
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Page/Page column 126; 127
(2015/07/07)
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- HETEROCYCLIC MODULATORS OF LIPID SYNTHESIS
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Heterocyclic modulators of lipid synthesis are provided as well as pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such compounds; and methods of treating conditions characterized by disregulation of a fatty acid synthase pathway by the administration of such compounds.
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Page/Page column 111; 112
(2014/01/18)
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- COMBINATIONS OF MEDICAMENTS, CONTAINING PDE4-INHIBITORS AND EP4-RECEPTOR-ANTAGONISTS
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The present invention relates to new medicament combinations which contain in addition to one or more PDE4-inhibitors (1) at least one EP4 receptor antagonist (2), as well as the use thereof for the treatment of preferably respiratory complaints such as particularly COPD, chronic sinusitis and asthma. The invention relates in particular to those medicament combinations which contain, in addition to one or more, preferably one, PDE4 inhibitor of general formula 1 wherein X is SO or SO2, but preferably SO, and wherein R1, R2, R3 and R4 have the meanings given in claim 1, at least one EP4 receptor antagonist (2), the preparation thereof and the use thereof for the treatment of respiratory complaints.
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Paragraph 0452; 0453
(2013/09/12)
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- DRUG COMBINATIONS CONTAINING PDE4 INHIBITORS AND NSAIDS
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The present invention relates to new drug combinations which contain in addition to one or more PDE4-inhibitors at least one NSAID (=non-steroidal anti-inflammatory drug) (2), processes for preparing them and their use in treating in particular respiratory complaints such as for example COPD, chronic sinusitis and asthma. The invention particularly relates to those drug combinations which contain, in addition to one or more, preferably one PDE4 inhibitor of general formula 1 wherein X is SO or SO2, but preferably SO, and wherein R1, R2, R3 and R4 have the meanings given in claim 1, at least one NSAID (2), the preparation thereof and the use thereof for the treatment of respiratory complaints.
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- Synthesis and SAR study of diphenylbutylpiperidines as cell autophagy inducers
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A novel series of diphenylbutylpiperidines as autophagy inducers was described and extensive SAR studies resulted in derivatives (15d-e, 15i-j) with 10-fold greater activity than the lead compounds 1 and 2. Meanwhile, a new synthetic route to diphenylbutyl bromide (6) from bromobenzene and γ-butyrolactone was also reported here.
- Chen, Gang,Xia, Hongguang,Cai, Yu,Ma, Dawei,Yuan, Junying,Yuan, Chengye
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scheme or table
p. 234 - 239
(2011/02/26)
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- DIPHENYLBUTYPIPERIDINE AUTOPHAGY INDUCERS
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Autophagy inducing compounds, methods of their preparation and use, and kits containg said compounds are disclosed herein.
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Page/Page column 7; 84-85
(2011/12/02)
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- 4-FLUORO-4-ARYLPIPERDIN-1-YL DERIVATIVES AS MU OPIOID FUNCTION MODERATORS
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4-Fluoro-4-phenylpiperidin-1-yl μ antagonists of general structure (I) are useful as treatments of conditions or diseases associated with binding opioid receptors.
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Page/Page column 19-20
(2011/11/13)
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- 5H-CYCLOPENTA[D]PYRIMIDINES AS AKT PROTEIN KINASE INHIBITORS
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Compounds of Formula I are useful for inhibiting AKT protein kinases. Methods of using compounds of Formula I and stereoisomers and pharmaceutically acceptable salts thereof, for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed. Formula (I).
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Page/Page column 59-60
(2009/09/04)
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- Cyclic hexapeptides having antibiotic activity
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This invention relates to new polypeptide compound represented by general formula (I), wherein R1, R2, R3, R4, R5 and R6 are as defined in the description or a salt thereof which has antimicrobial activities (especially, antifungal activities), inhibitory activity on β-1,3-glucan synthase, to process for preparation thereof, to a pharmaceutical composition comprising the same, and to a method for prophylactic and/or therapeutic treatment of infectious diseases including Pneumocystis carinii infection (e.g. Pneumocystis carinii pneumonia) in a human being or an animal.
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- Design and synthesis of orally active inhibitors of TNF synthesis as anti-rheumatoid arthritis drugs
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A novel series of TNF inhibitors was identified based on the screening of existing MMP inhibitor libraries. Further SAR optimization led to the discovery of a novel lead compound. Its synthesis, efficacy in experimental animal models, and pharmacokinetic
- Chen, Jian Jeffrey,Dewdney, Nolan,Lin, Xiaohong,Martin, Robert L.,Walker, Keith A. M.,Huang, Jane,Chu, Frances,Eugui, Elsie,Mirkovich, Anna,Kim, Yong,Sarma, Keshab,Arzeno, Humberto,Van Wart, Harold E.
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p. 3951 - 3954
(2007/10/03)
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- Chemical modification of aryl-1,2,3,6-tetrahydropyridinopyrimidine derivative to discover corticotropin-releasing factor1 receptor antagonists: Aryl-1,2,3,6-tetrahydropyridino-purine, -3H-1,2,3-triazolo[4,5-d]pyrimidine, -purin-8-one, and -7H-pyrrolo[2,3-d]pyrimidine derivatives
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Structure-affinity relationships (SARs) of non-peptide CRF1 antagonists suggest that such antagonists can be constructed of three units: a hydrophobic unit (Up-Area), a proton accepting unit (Central-Area), and an aromatic unit (Down-Area). Recently, various non-peptide corticotropin-releasing factor1 (CRF1) receptor antagonists obtained by modification of the Central-Area have been reported. In contrast, we modified the Up-Area and presented 4- or 5-aryl-1,2,3,6-tetrahydropyridinopyrimidine derivatives including potent CRF receptor ligands 1a-c, and proposed that the 4- or 5-aryl-1,2,3,6-tetrahydropyridino moiety might be useful as a substituent in the Up-Area. Our interest shifted to the chemical modification in which the pyrimidine ring of 1a-c was replaced by other heterocycles, purine ring of 2, 3H-1,2,3-triazolo[4,5-d]pyrimidine ring of 3, purin-8-one ring of 4 and 7H-pyrrolo[2,3-d]pyrimidine ring of 5. Among them, 5-aryl-1,2,3,6-tetrahydropyridinopurine compound 6j (CRA0186) had the highest affinity for CRF1 receptors (IC50=20 nM). We report here the synthesis and SARs of derivatives 6-9.
- Kumagai, Toshihito,Okubo, Taketoshi,Kataoka-Okubo, Hiromi,Chaki, Shigeyuki,Okuyama, Shigeru,Nakazato, Atsuro
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p. 1357 - 1363
(2007/10/03)
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- Synthesis and dopaminergic activity of some 3-(1,2,3,6-tetrahydro-1- pyridylalkyl)indoles. A novel conformational model to explain structure- activity relationships
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The synthesis and dopaminergic properties of a novel type of dopamine agonist is described. The number and kind of essential structural elements differ significantly from that of the rigid apomorphine-type dopamine agonists. Using standard molecular modeling techniques, a conformational model is developed proposing a U-shaped conformation which might be energetically preferred through aromatic π-π-interactions between both of the electron rich aromatic structural elements of this class of compounds. Superimposition of conformations of the lead compound 28 with apomorphine yields a novel model explaining the atypical structure-activity relationships found in this class of indolealkylamines.
- Bottcher,Barnickel,Hausberg,Haase,Seyfried,Eiermann
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p. 4020 - 4026
(2007/10/02)
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