Novel S1P1 receptor agonists – Part 5: From amino-to alkoxy-pyridines

Bolli, Martin H.; Lescop, Cyrille; Birker, Magdalena; Kanter, Ruben de; Hess, Patrick; Kohl, Christopher; Nayler, Oliver; Rey, Markus; Sieber, Patrick; Velker, Jörg; Weller, Thomas; Steiner, Beat

doi:10.1016/j.ejmech.2016.03.020

Cited by 16 publications

(18 citation statements)

References 87 publications

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“…Consequently, nonselective S1P 1 receptor modulators were shown to be associated with adverse events, including bradycardia, atrioventricular conduction block, mild hypertension, and dyspnea. 3,4,17,21,22,[28][29][30] Here, we show that cenerimod is a novel, potent and selective S1P 1 receptor modulator with unique signaling properties. Cenerimod, in comparison to S1P and pFTY720, was devoid of S1P 2 receptor agonism in ( 35 S)-GTPcS assays up to the highest tested concentration.…”

Section: Discussionmentioning

confidence: 73%

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Cenerimod, a novel selective S1P₁ receptor modulator with unique signaling properties

Piali

Birker‐Robaczewska

Lescop

et al. 2017

Pharmacology Res & Perspec

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Sphingosine‐1‐phosphate receptor 1 (S1P1) modulators sequester circulating lymphocytes within lymph nodes, thereby preventing potentially pathogenic autoimmune cells from exiting into the blood stream and reaching inflamed tissues. S1P1 receptor modulation may thus offer potential to treat various autoimmune diseases. The first nonselective S1P1‐5 receptor modulator FTY720/fingolimod/Gilenya® has successfully demonstrated clinical efficacy in relapsing forms of multiple sclerosis. However, cardiovascular, hepatic, and respiratory side‐effects were reported and there is a need for novel S1P1 receptor modulators with better safety profiles. Here, we describe the discovery of cenerimod, a novel, potent and selective S1P1 receptor modulator with unique S1P1 receptor signaling properties and absence of broncho‐ and vasoconstrictor effects ex vivo and in vivo. Cenerimod dose‐dependently lowered circulating lymphocyte counts in rats and mice after oral administration and effectively attenuated disease parameters in a mouse experimental autoimmune encephalitis (EAE) model. Cenerimod has potential as novel therapy with improved safety profile for autoimmune diseases with high unmet medical need.

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Section: Discussionmentioning

confidence: 73%

“…Furthermore, the S1P receptor family consists of five members with divergent tissue expression. Consequently, nonselective S1P 1 receptor modulators were shown to be associated with adverse events, including bradycardia, atrioventricular conduction block, mild hypertension, and dyspnea …”

Section: Discussionmentioning

confidence: 99%

Cenerimod, a novel selective S1P₁ receptor modulator with unique signaling properties

Piali

Birker‐Robaczewska

Lescop

et al. 2017

Pharmacology Res & Perspec

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“…At 24 the 2-pyridines clearly lose activity while most of the 4-pyridines retain full efficacy. [79][80][81]…”

Section: Key Properties Of Macitentanmentioning

confidence: 99%

The Discovery of Macitentan – A Standard Medicinal Chemistry Program?

Bolli

2017

Chimia

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A plethora of properties are typically studied during a medicinal chemistry program and many of these parameters may shape the cascade of compound selection. Given the task to discover a molecule with a profile superior to that of the dual endothelin receptor antagonist bosentan, we tailored our compound profiling cascade to the specific properties that were not optimal in bosentan, namely in vivo efficacy and safety. Contrary to conventional thinking, we therefore focused on corresponding in vivo experiments. In the following, we highlight and illustrate some key learnings of our approach that led to the discovery of macitentan (1), an orally available potent dual endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension.

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“…Taking into account the aforementioned considerations, we have turned our attention to functionalized pyridylcyclobutanes as attractive chemotypes for design of biologically active compounds. The known approaches to the synthesis of pyridylcyclobutane derivatives include metal‐catalyzed sp 2 ‐sp 3 cross‐couplings of halopyridines, reactions of metallated pyridines, the Minisci or the Barton radical reactions, transformations of pyridine N ‐oxides or their derivatives, as well as other methods . However, most literature examples relied on the [2 + 2] cycloadditions, including photodimerization, intra‐ and intermolecular reactions.…”

Section: Introductionmentioning

confidence: 99%

Robust and Scalable Approach to 1,3‐Disubstituted Pyridylcyclobutanes

et al. 2019

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An approach to all isomeric 3‐pyridylcyclobutane‐derived building blocks, i.e. ketones, alcohols and amines, is described. Synthesis of the title compounds relied on the five‐step reaction sequence including alkylation of isomeric pyridyl acetonitriles with 1,3‐dibromo‐2,2‐dimethoxypropane. Hydrolysis, decarboxylation and removal of the ketal moiety led to the key 3‐pyridylcyclobutanones (obtained on up to 120 g scale in a single run), which were transformed into the corresponding alcohols and amines with high diastereoselectivity. The title cyclobutanone derivatives were used to synthesize three isomeric nicotine analogues, as well as for parallel synthesis of a small lead‐like compound library via reductive amination.

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Novel S1P1 receptor agonists – Part 5: From amino-to alkoxy-pyridines

Cited by 16 publications

References 87 publications

Cenerimod, a novel selective S1P₁ receptor modulator with unique signaling properties

Cenerimod, a novel selective S1P₁ receptor modulator with unique signaling properties

The Discovery of Macitentan – A Standard Medicinal Chemistry Program?

Robust and Scalable Approach to 1,3‐Disubstituted Pyridylcyclobutanes

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Novel S1P1 receptor agonists – Part 5: From amino-to alkoxy-pyridines

Cited by 16 publications

References 87 publications

Cenerimod, a novel selective S1P1 receptor modulator with unique signaling properties

Cenerimod, a novel selective S1P1 receptor modulator with unique signaling properties

The Discovery of Macitentan – A Standard Medicinal Chemistry Program?

Robust and Scalable Approach to 1,3‐Disubstituted Pyridylcyclobutanes

Contact Info

Product

Resources

About

Cenerimod, a novel selective S1P₁ receptor modulator with unique signaling properties

Cenerimod, a novel selective S1P₁ receptor modulator with unique signaling properties