- A fluorescent activatable probe for imaging intracellular Mg2+
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An activatable BODIPY probe for in vitro detection and fluorescence cell imaging of free Mg2+ without interference from Ca2+ is described. Fluorescence amplification of the probe is observed upon detection of physiological concentrations of Mg2+ due to reduced rotation of the fluorophore and effective chelation by a quinolizine-based core.
- Treadwell, Ryan,De Moliner, Fabio,Subiros-Funosas, Ramon,Hurd, Toby,Knox, Kirsten,Vendrell, Marc
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p. 239 - 244
(2018/01/12)
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- Discovery of a selective allosteric M1 receptor modulator with suitable development properties based on a quinolizidinone carboxylic acid scaffold
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One approach to ameliorate the cognitive decline in Alzheimer's disease (AD) has been to restore neuronal signaling from the basal forebrain cholinergic system via the activation of the M1 muscarinic receptor. A number of nonselective M1 muscarinic agonists have previously shown positive effects on cognitive behaviors in AD patients, but were limited due to cholinergic adverse events thought to be mediated by the activation of the M2 to M5 subtypes. One strategy to confer selectivity for M1 is the identification of positive allosteric modulators, which would target an allosteric site on the M1 receptor rather than the highly conserved orthosteric acetylcholine binding site. Quinoline carboxylic acids have been previously identified as highly selective M1 positive allosteric modulators with good pharmacokinetic and in vivo properties. Herein is described the optimization of a novel quinolizidinone carboxylic acid scaffold with 4-cyanopiperidines being a key discovery in terms of enhanced activity. In particular, modulator 4i gave high plasma free fractions, enhanced central nervous system (CNS) exposure, was efficacious in a rodent in vivo model of cognition, and afforded good physicochemical properties suitable for further preclinical evaluation.
- Kuduk, Scott D.,Chang, Ronald K.,Di Marco, Christina N.,Pitts, Daniel R.,Greshock, Thomas J.,Ma, Lei,Wittmann, Marion,Seager, Matthew A.,Koeplinger, Kenneth A.,Thompson, Charles D.,Hartman, George D.,Bilodeau, Mark T.,Ray, William J.
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experimental part
p. 4773 - 4780
(2011/09/20)
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- Quinolizidinone carboxylic acid selective M1 allosteric modulators: SAR in the piperidine series
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SAR study of the piperidine moiety in a series of quinolizidinone carboxylic acid M1 positive allosteric modulators was examined. While the SAR was generally flat, compounds were identified with high CNS exposure to warrant additional in vivo evaluation.
- Kuduk, Scott D.,Chang, Ronald K.,Di Marco, Christina N.,Ray, William J.,Ma, Lei,Wittmann, Marion,Seager, Matthew A.,Koeplinger, Kenneth A.,Thompson, Charles D.,Hartman, George D.,Bilodeau, Mark T.
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scheme or table
p. 1710 - 1715
(2011/05/05)
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- Quinolizidinone carboxylic acids as CNS penetrant, selective M1 allosteric muscarinic receptor modulators
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Positive allosteric modulation of the M1 muscarinic receptor represents an approach to treat the cognitive decline in patients with Alzheimer's disease. Replacement of a quinolone ring system in a quinolone carboxylic acid series of M1 modulators with a quinolizidinone bearing a basic amine linkage led to a series of compounds with higher free fraction, enhanced CNS exposure, and improved efficacy in rodent in vivo models of cognition.
- Kuduk, Scott D.,Chang, Ronald K.,Di Marco, Christina N.,Ray, William J.,Ma, Lei,Wittmann, Marion,Seager, Matthew A.,Koeplinger, Kenneth A.,Thompson, Charles D.,Hartman, George D.,Bilodeau, Mark T.
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scheme or table
p. 263 - 267
(2010/11/18)
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- Design, synthesis and anti-HIV integrase evaluation of 4-oxo-4H- quinolizine-3-carboxylic acid derivatives
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4-Oxo-4H-quinolizine-3-carboxylic acid derivatives bearing sulfamido, carboxylamido, benzimidazole and benzothiazole substituents have been designed and synthesized. The structures of these new compounds were confirmed by 1H-NMR, 13C
- Xu, Yi-Sheng,Zeng, Cheng-Chu,Jiao, Zi-Guo,Hu, Li-Ming,Zhong, Ru-Gang
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scheme or table
p. 868 - 883
(2009/05/27)
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- COMPOUNDS TO TREAT AMYLOIDOSIS AND PREVENT DEATH OF BETA-CELLS IN TYPE 2 DIABETES MELLITUS
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The invention discloses aromatic amides and sulfonates to treat or prevent type 2 diabetes mellitus (T2DM), the pathological consequences of T2DM, to inhibit amyloidosis or to prevent death of β-cells of the pancreas.
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Page/Page column 46
(2010/11/24)
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- Quinolizinone compounds and pharmaceutical composition comprising the same, useful as anti-ulcerative and anti-allergic agents
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The invention relates to novel quinolizinone compounds having inhibitory activity on allergies and ulcers, of the formula: STR1 wherein R1 is tetrazolylcarbamoyl; R7 is hydrogen or aryl selected from phenyl, tolyl, xylyl, cumenyl, naphthyl and biphenylyl; R2 is hydrogen, hydroxy, lower alkyl or lower alkoxy; R3 is hydrogen, hydroxy, lower alkyl, lower alkoxy, lower alkenyloxy, phenyl, napthyl, biphenylyl, phenyl having one or more substituent(s) selected from halogen, lower alkyl and lower alkoxy, arylthio selected from phenylthio, tolylthio, xylylthio, cumenylthio, naphthylthio and biphenylthio, aroyl selected from benzoyl, toluoyl and naphthoyl, ar(lower)alkyl selected from phenyl(lower)alkyl, tolyl(lower)alkyl, xylyl(lower)alkyl, cumenyl(lower)alkyl, naphthyl(lower)alkyl and biphenylyl(lower)alkyl, arenesulfonyl selected from benzenesulfonyl and p-toluenesulfonyl, arylamino selected from phenylamino, naphthylamino, biphenylylamino, phenylamino having lower alkyl on the nitrogen atom or aryloxy selected from phenoxy and tolyloxy; or pharmaceutically acceptable salts thereof.
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