- Novel S1P1 receptor agonists - Part 3: From thiophenes to pyridines
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In preceding communications we summarized our medicinal chemistry efforts leading to the identification of potent, selective, and orally active S1P 1 agonists such as the thiophene derivative 1. As a continuation of these efforts, we replaced the thiophene in 1 by a 2-, 3-, or 4-pyridine and obtained less lipophilic, potent, and selective S1P1 agonists (e.g., 2) efficiently reducing blood lymphocyte count in the rat. Structural features influencing the compounds' receptor affinity profile and pharmacokinetics are discussed. In addition, the ability to penetrate brain tissue has been studied for several compounds. As a typical example for these pyridine based S1P 1 agonists, compound 53 showed EC50 values of 0.6 and 352 nM for the S1P1 and S1P3 receptor, respectively, displayed favorable PK properties, and penetrated well into brain tissue. In the rat, compound 53 maximally reduced the blood lymphocyte count for at least 24 h after oral dosing of 3 mg/kg.
- Bolli, Martin H.,Abele, Stefan,Birker, Magdalena,Bravo, Roberto,Bur, Daniel,De Kanter, Ruben,Kohl, Christopher,Grimont, Julien,Hess, Patrick,Lescop, Cyrille,Mathys, Boris,Müller, Claus,Nayler, Oliver,Rey, Markus,Scherz, Michael,Schmidt, Gunther,Seifert, Jürgen,Steiner, Beat,Velker, J?rg,Weller, Thomas
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supporting information
p. 110 - 130
(2014/02/14)
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- PYRIDIN-4-YL DERIVATIVES
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The invention relates to compounds of the Formula (I), Formula (I) wherein R1 and R2 are as described in the description, their preparation and their use as pharmaceutically active compounds. Said compounds particularly act as immuno
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Page/Page column 17; 18
(2014/09/29)
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- Discovery of novel series of 6-benzyl substituted 4-aminocarbonyl-1,4- diazepane-2,5-diones as human chymase inhibitors using structure-based drug design
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A novel series of 6-benzyl substituted 4-aminocarbonyl-1,4-diazepane-2,5- diones were explored as human chymase inhibitors using structure-based drug design according to the X-ray cocrystal structure of chymase and compound 1. The optimization focused on
- Tanaka, Taisaku,Sugawara, Hajime,Maruoka, Hiroshi,Imajo, Seiichi,Muto, Tsuyoshi
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p. 4233 - 4249
(2013/07/27)
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- PTERIDINES AND THEIR USE AS AGROCHEMICALS
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The present disclosure relates to 1- or 2-(4-(aryloxy)-phenyl)ethylamino-, oxy- or sulfanyl)pteridines and 1- or 2-(4-(heteroaryloxy)-phenyl)ethylamino-, oxy- or sulfanyl)pteridines and their use as agrochemicals and animal health products.
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Page/Page column 29
(2011/04/14)
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- PTERIDINES AND THEIR USE AS AGROCHEMICALS
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The present disclosure relates to 1- or 2-(4-(aryloxy)-phenyl)ethylamino-, oxy- or sulfanyl)pteridines and 1- or 2-(4-(heteroaryloxy)-phenyl)ethylamino-, oxy- or sulfanyl)pteridines and their use as agrochemicals and animal health products.
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Page/Page column 62
(2011/04/14)
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- Development of a scalable synthesis of dipeptidyl peptidase-4 inhibitor ABT-279
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A convergent, scalable synthesis of dipeptidyl peptidase-4 inhibitor, ABT-279, has been developed and demonstrated on multikilogram scale. The cis-2,5-disubstituted pyrrolidine is generated by cyclization of a Boc-amine onto an alkynyl ketone followed by stereospecific reduction of the resulting acyliminium intermediate. The amine coupling partner was prepared by a novel Hofmann rearrangement promoted by 1,3-dibromo-5,5-dimethylhydantoin. The final product was isolated as the L-malic acid salt. The scaleup campaign consisted of 15 steps and delivered 42 kg of ABT-279 in 14% overall yield. A second-generation synthesis that addresses some of the issues encountered during scale-up was developed and demonstrated on kilogram scale.
- McDermott, Todd S.,Bhagavatula, Lakshmi,Borchardt, Thomas B.,Engstrom, Kenneth M.,Gandarilla, Jorge,Kotecki, Brian J.,Kruger, Albert W.,Rozema, Michael J.,Sheikh, Ahmad Y.,Wagaw, Seble H.,Wittenberger, Steven J.
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experimental part
p. 1145 - 1155
(2010/04/22)
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- SYNTHESIS OF (2S,5R)-5-ETHYNYL-1-{N-(4-METHYL-1-(4-CARBOXY-PYRIDIN-2-YL)PIPERIDIN-4-YL)GLYCYL}PYRROLIDINE-2-CARBONITRILE
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A process for making (2S,5R)-5-ethynyl-1-{N-(4-methyl-1-(4-carboxy-pyridin-2-yl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile and salts thereof, and intermediates used in the process are disclosed.
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Page/Page column 37
(2008/06/13)
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- Macrocyclic Compounds Useful as Bace Inhibitors
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The invention relates to novel macrocyclic compounds of the formula (I), in which all of the variables are as defined in the specification, the number of ring atoms included in the macrocyclic ring being 14, 15, 16 or 17, in free base form or in acid addition salt form, to their preparation, to their use as medicaments and to medicaments comprising them.
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Page/Page column 28
(2008/12/05)
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- HETEROCYCLIC CYTOKINE INHIBITORS
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The present invention provides low molecular weight compounds useful as cytokine inhibitors, and compositions thereof. In particular, compounds of the invention are useful as anti-inflammatory, anti-pain or anti-cancer agents. There are further provided m
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Page/Page column 132
(2010/11/27)
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- Amide derivatives
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The invention concerns amide derivatives of the Formula I wherein X is CH or N; Y is CH or N; m is 0-3; R1is a group such as hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy and carbamoyl; n is 0-3; R2is a group such as hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy and (1-6C)alkoxycarbonyl; R3is hydrogen, halogeno, (1-6C)alkyl or (1-6C)alkoxy; q is 0-4; and Q is a group such as aryl, aryloxy, aryl-(1-6C)alkoxy, arylamino,N-(1-6C)alkyl-arylamino and aryl-(1-6C)alkylamino; or pharmaceutically-acceptable salts or in-vivo-cleavable esters thereof; processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical conditions mediated by cytokines.
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