- Bis(het)aryl-1,2,3-triazole quinuclidines as α7 nicotinic acetylcholine receptor ligands: Synthesis, structure affinity relationships, agonism activity, [18F]-radiolabeling and PET study in rats
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In this paper we describe the design and synthesis of bis(Het)Aryl-1,2,3-triazole quinuclidine α7R ligands using an efficient three-step sequence including a Suzuki-Miyaura cross coupling reaction with commercially available and home-made boron derivatives. The exploration of SAR required the preparation of uncommon boron derivatives. Forty final drugs were tested for their ability to bind the target and nine of them exhibited Ki values below nanomolar concentrations. The best scores were always obtained when the 5-phenyl-2-thiophenyl core was attached to the triazole. The selectivity of these compounds towards the nicotinic α4β2 and serotoninergic 5HT3 receptors was assessed and their brain penetration was quantified by the preparation and in vivo evaluation of two [18F] radiolabelled derivatives. It can be expected from our results that some of these compounds will be suitable for further developments and will have effects on cognitive disorders.
- Ouach, Aziz,Vercouillie, Johnny,Bertrand, Emilie,Rodrigues, Nuno,Pin, Frederic,Serriere, Sophie,Boiaryna, Liliana,Chartier, Agnes,Percina, Nathalie,Tangpong, Pakorn,Gulhan, Zuhal,Mothes, Celine,Deloye, Jean-Bernard,Guilloteau, Denis,Page, Guylene,Suzenet, Franck,Buron, Frederic,Chalon, Sylvie,Routier, Sylvain
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p. 449 - 469
(2019/07/03)
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- Design and synthesis of benzopyran-based inhibitors of the hypoxia-inducible factor-1 pathway with improved water solubility
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While progress has been made in treating cancer, cytotoxic chemotherapeutic agents are still the most widely used drugs and are associated with severe side-effects. Drugs that target unique molecular signalling pathways are needed for treating cancer with low or no intrinsic toxicity to normal cells. Our goal is to target hypoxic tumours and specifically the hypoxia inducible factor (HIF) pathway for the development of new cancer therapies. To this end, we have previously developed benzopyran-based HIF-1 inhibitors such as arylsulfonamide KCN1. However, KCN1 and its earlier analogs have poor water solubility, which hamper their applications. Herein, we describe a series of KCN1 analogs that incorporate a morpholine moiety at various positions. We found that replacing the benzopyran group of KCN1 with a phenyl group with a morpholinomethyl moiety at the para positions had minimal effect on potency and improved the water solubility of two new compounds by more than 10-fold compared to KCN1, the lead compound.
- Ferguson, Jalisa H.,De Los Santos, Zeus,Devi, Saroja N.,Kaluz, Stefan,Van Meir, Erwin G.,Zingales, Sarah K.,Wang, Binghe
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p. 992 - 1001
(2017/08/09)
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- CYCLOALKYL NITRILE PYRAZOLO PYRIDONES AS JANUS KINASE INHIBITORS
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Compounds of formula I are provided, which are JAK inhibitors and are useful for the treatment of JAK-mediated diseases such as rheumatoid arthritis, asthma, COPD and cancer.
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Page/Page column 83
(2014/10/03)
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- CYCLOALKYL NITRILE PYRAZOLO PYRIDONES AS JANUS KINASE INHIBITORS
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The instant invention provides compounds of formula I which are JAK inhibitors, and as such are useful for the treatment of JAK-mediated diseases such as rheumatoid arthritis, asthma, COPD and cancer.
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Page/Page column 70
(2014/10/03)
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- SUBSTITUTED PYRIDINE DERIVATIVES AS FABI INHIBITORS
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The present invention provides substituted pyridine derivatives of formula (I), which may be therapeutically useful as as anti-bacterial agents, more particulalrly FabI inhibitors. Formula(I) in which R1 to R5 and L have the meanings given in the specification, and pharmaceutically acceptable salts thereof that are useful in the treatment and prevention in diseases or disorder, in particular their use in diseases or disorder where there is an advantage anti-bacterial agents, more particularly FabI inhibitors. The present invention also provides methods for synthesizing and administering the FabI inhibitor compounds. The present invention also provides pharmaceutical formulations comprising at least one of the FabI inhibitor compounds together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
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Page/Page column 35-36
(2013/06/27)
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- TRIAZOLOPYRIDINE COMPOUNDS
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A compound of formula (Ia): or a pharmaceutically acceptable salt and/or solvate (including hydrate) thereof, or a compound of formula (Ib): or a pharmaceutically acceptable salt and/or solvate (including hydrate) thereof, and the use of a compound of formula (Ia) or (Ib) in the treatment of a TNF -mediated disease, disorder, or condition, or a p38 -mediated disease,. disorder, or condition, in particular the allergic and non-allergic airway diseases, more particularly obstructive or inflammatory airways diseases, preferably chronic obstructive pulmonary disease.
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Page/Page column 46
(2008/06/13)
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- New modifications to the area of pyrazole-naphthyl urea based p38 MAP kinase inhibitors that bind to the adenine/ATP site
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Discovery of the pyrazole-naphthyl urea class of p38 MAP kinase inhibitors typified by the clinical candidate BIRB 796 has encouraged further exploration of this particular scaffold. Modification to the part of the inhibitor that occupies the adenine/ATP
- Moss, Neil,Breitfelder, Steffen,Betageri, Raj,Cirillo, Pier F.,Fadra, Tazmeen,Hickey, Eugene R.,Kirrane, Thomas,Kroe, Rachel R.,Madwed, Jeffrey,Nelson, Richard M.,Pargellis, Christopher A.,Qian, Kevin C.,Regan, John,Swinamer, Alan,Torcellini, Carol
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p. 4242 - 4247
(2008/02/09)
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- Development of high-load, soluble oligomeric sulfonate esters via ROM polymerization: Application to the benzylation of amines
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The development of high-load, soluble oligomeric sulfonate esters, generated via ROM polymerization, and their utility in the facile benzylation of an array of amines is reported. These polymeric sulfonate esters exist as free-flowing powders, are stable
- Zhang, Mianji,Moore, Joel D.,Flynn, Daniel L.,Hanson, Paul R.
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p. 2657 - 2660
(2007/10/03)
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- Substituted 4-anilino-7-phenyl-3-quinolinecarbonitriles as Src kinase inhibitors
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A series of substituted 4-anilino-7-phenyl-3-quinolinecarbonitriles has been prepared as Src kinase inhibitors. Optimal activity is observed with compounds that have basic amines attached via the para position of the 7-phenyl ring, and a hydrogen atom at the C-6 position. The best compounds are low nanomolar inhibitors of Src kinase, and have potent activity against Src-transformed fibroblast cells.
- Berger, Dan,Dutia, Minu,Powell, Dennis,Wissner, Allan,DeMorin, Frenel,Raifeld, Yuri,Weber, Jennifer,Boschelli, Frank
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p. 2989 - 2992
(2007/10/03)
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- 3-cyanoquinolines, 3-cyano-1,6-naphthyridines, and 3-cyano-1,7-naphthyridines as protein kinase inhibitors
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This invention provides compounds of Formula (I), having the structure where T, Z, X, A, R1, R2a, R2b, R2c, R3, R4, and n are defined herein, or a pharmaceutically acceptable salt thereof which are useful as antineoplastic agents and in the treatment of osteoporosis and polycystic kidney disease.
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