- Novel S1P1 receptor agonists - Part 4: Alkylaminomethyl substituted aryl head groups
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In a previous communication we reported on the discovery of alkylamino pyridine derivatives (e.g. 1) as a new class of potent, selective and efficacious S1P1 receptor (S1PR1) agonists. However, more detailed profiling revealed that this compound class is phototoxic in vitro. Here we describe a new class of potent S1PR1 agonists wherein the exocyclic nitrogen was moved away from the pyridine ring (e.g. 11c). Further structural modifications led to the identification of novel alkylaminomethyl substituted phenyl and thienyl derivatives as potent S1PR1 agonists. These new alkylaminomethyl aryl compounds showed no phototoxic potential. Based on their in vivo efficacy and ability to penetrate the brain, the 5-alkyl-aminomethyl thiophenes appeared to be the most interesting class. Potent and selective S1PR1 agonist 20e, for instance, maximally reduced the blood lymphocyte count (LC) for 24 h after oral administration of 10 mg/kg to rat and its brain concentrations reached >500 ng/g over 24 h.
- Lescop, Cyrille,Müller, Claus,Mathys, Boris,Birker, Magdalena,De Kanter, Ruben,Kohl, Christopher,Hess, Patrick,Nayler, Oliver,Rey, Markus,Sieber, Patrick,Steiner, Beat,Weller, Thomas,Bolli, Martin H.
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p. 222 - 238
(2016/04/20)
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- SPIRO-SUBSTITUTED OXINDOLE DERIVATIVES HAVING AMPK ACTIVITY
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The present invention relates to compounds of formula (I), which have valuable pharmacological properties, in particular are activators of AMPK and which are therefore useful in the treatment of certain disorders that can be prevented or treated by activation of this receptor. The compounds are suitable for treatment and prevention of diseases which can be influenced by this receptor, such as metabolic diseases, in particular diabetes type 2.
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Page/Page column 78
(2015/01/07)
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- OLEFIN SUBSTITUTED OXINDOLES HAVING AMPK ACTIVITY
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The present invention relates to compounds of formula (I), which have valuable pharmacological properties, in particular are activators of AMPK and which are therefore useful in the treatment of certain disorders that can be prevented or treated by activation of this receptor. The compounds are suitable for treatment and prevention of diseases which can be influenced by this receptor, such as metabolic diseases, in particular diabetes type 2.
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Page/Page column 63; 64
(2015/01/07)
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- PYRIMIDINE COMPOUNDS AND METHODS OF USE
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The invention provides pyrimidine compounds having formula (A): The pyrimidine compounds of the invention are capable of inhibiting kinases, such as members of the Src kinase family, and various other specific receptor and non-receptor kinases.
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Page/Page column 112-113
(2010/11/24)
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- HIV protease inhibitors
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HIV protease inhibitors, obtainable by chemical synthesis, inhibit or block the biological activity of the HIV protease enzyme, causing the replication of the HIV virus to terminate. These compounds, as well as pharmaceutical compositions that contain these compounds and optionally other anti-viral agents as active ingredients, are suitable for treating patients or hosts infected with the HIV virus, which is known to cause AIDS.
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- HIV protease inhibitors
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HIV protease inhibitors, obtainable by chemical synthesis, inhibit or block the biological activity of the HIV protease enzyme, causing the replication of the HIV virus to terminate. These compounds, as well as pharmaceutical compositions that contain these compounds and optionally other anti-viral agents as active ingredients, are suitable for treating patients or hosts infected with the HIV virus, which is known to cause AIDS.
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- Microbial Stereodifferentiating Reduction of (+/-)4-Methyl- and (+/-)-6-Methyl-1-oxometacyclophanes and Revision of the Absolute Configuration of 4-Substituted Metacyclophanes
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Partial oxidative hydrolysis of 4-bromo-1,1,10,10-bis(trimethylenedithio)metacyclophane (7) yielded the bromo ketones 8 and 9 which were respectively converted into (+/-)-4-methyl- (3) and (+/-)-6-methyl-1-oxometacyclophanes (4).The unambiguous synthesis of (+/-)-3 from 2,5-dimethylbenzoic acid (18) assigned their structures.Incubation of (+/-)-3 with Rhodotorula rubra gave a mixture of (-)-ketone 3, (-) axial alcohol 38, and (-) equatorial alcohol 39.The observed (-) Cotton effect indicated the pS configuration of (-)-3, and transformation of (-)-3 into (+)-4-methylmetacyclophane (5) permitted the assignment of the pR configuration to (+)-5, opposite to Schloegl's proposal.This conclusion was further supported by the parallel sequence of the steps starting from (+/-)-6-methyl ketone.
- Nakazaki, Masao,Hirose, Yoshiki,Shimizu, Toru,Suzuki, Takaaki,Ishii, Akira,Makimura, Masaru
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p. 1428 - 1435
(2007/10/02)
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