Design, synthesis and activity of novel derivatives of Oxybutynin and Tolterodine

Kaur, Kirandeep; Aeron, Shelly; Miriyala, Bruhaspathy; Shetty, Shankar J.; Gupta, Suman; Hegde, Laxminarayan H.; Silamkoti, Arun D.V.; Mehta, A. G.; Chugh, Anita; Gupta, Jang B.; Sarma, Parismita; Kumar, Naresh

doi:10.1016/j.bmcl.2005.02.036

Cited by 11 publications

(11 citation statements)

References 5 publications

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“…The crude residue was purified by flash chromatography eluting with a mixture of petroleum ether/ethyl acetate in variable proportion, to give the desired product as a white solid in yields ranging from 65% to 78%. Analytical data for compounds 13 and 16 matched the data already published 46 . …”

Section: General Procedures For the Synthesis Of Esters 13-18supporting

confidence: 77%

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Cyclopropane-1,2-dicarboxylic acids as new tools for the biophysical investigation ofO-acetylserine sulfhydrylases by fluorimetric methods and saturation transfer difference (STD) NMR

Annunziato¹,

Pieroni²,

Benoni

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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Cysteine is a building block for many biomolecules that are crucial for living organisms. O-Acetylserine sulfhydrylase (OASS), present in bacteria and plants but absent in mammals, catalyzes the last step of cysteine biosynthesis. This enzyme has been deeply investigated because, beside the biosynthesis of cysteine, it exerts a series of ''moonlighting'' activities in bacteria. We have previously reported a series of molecules capable of inhibiting Salmonella typhimurium (S. typhymurium) OASS isoforms at nanomolar concentrations, using a combination of computational and spectroscopic approaches. The cyclopropane-1,2-dicarboxylic acids presented herein provide further insights into the binding mode of small molecules to OASS enzymes. Saturation transfer difference NMR (STD-NMR) was used to characterize the molecule/ enzyme interactions for both OASS-A and B. Most of the compounds induce a several fold increase in fluorescence emission of the pyridoxal 5 0 -phosphate (PLP) coenzyme upon binding to either OASS-A or OASS-B, making these compounds excellent tools for the development of competition-binding experiments.

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Section: General Procedures For the Synthesis Of Esters 13-18supporting

confidence: 77%

“…Following a similar procedure, but using equimolar amount of KOH and EtOH as the solvent, title compound 25 was obtained from 15 in 64% yield. Analytical data for compounds 19 and 22 matched those already published 46 .…”

Section: General Procedures For the Synthesis Of Derivatives 19-24supporting

confidence: 73%

Cyclopropane-1,2-dicarboxylic acids as new tools for the biophysical investigation ofO-acetylserine sulfhydrylases by fluorimetric methods and saturation transfer difference (STD) NMR

Annunziato¹,

Pieroni²,

Benoni

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…The most recent studies on oxybutynin structure (Table VIII) involve the introduction of a different basic moiety, as described by Ranbaxy, 81 which replaced the simple pyrrolidinium subunit with a bridged bicyclical tertiary amine. These bicyclic pyrrolidine derivatives are quite potent (with binding affinity in the low nanomolar range) but not selective toward the M2 receptor.…”

Section: A Oxybutynin Analoguesmentioning

confidence: 99%

Medicinal chemistry and therapeutic potential of muscarinic M3 antagonists

Peretto¹,

Petrillo²,

Imbimbo

2009

Medicinal Research Reviews

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Muscarinic acetylcholine receptors belong to the G-protein-coupled receptors family. Currently five different receptor subtypes have been identified and cloned. M3 receptor subtypes are coupled to G(q) family proteins and increase phosphatidyl inositol hydrolysis and calcium release from internal stores. They are widely distributed both in the central nervous system and in the periphery. At the central level, M3 receptor subtypes are involved in modulation of neurotransmitter release, temperature homeostasis, and food intake, while in the periphery they induce smooth muscle contraction, gland secretion, indirect relaxation of vascular smooth muscle, and miosis. The main therapeutic applications of M3 antagonists include overactive bladder (OAB), chronic obstructive pulmonary disease (COPD), and pain-predominant irritable bowel syndrome (IBS). The introduction of selective M3 antagonists has not improved clinical efficacy compared with the old non-selective antimuscarinics but has reduced the rate of adverse events mediated by the blockade of cardiac M2 receptors (tachycardia) and central M1 receptors (cognitive impairment). Improved tolerability has been obtained also with controlled release or with inhaled formulations. However, there is still a need for safer M3 antagonists for the treatment of COPD and better-tolerated and more effective compounds for the therapy of OAB. New selective muscarinic M3 antagonists currently in early discovery and under development have been designed to address these issues. However, as M3 receptors are widely located in various tissues including salivary glands, gut smooth muscles, iris, and ciliary muscles, further clinical improvements may derive from the discovery and the development of new compounds with tissue rather than muscarinic receptor subtype selectivity.

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“…Recent research in this area includes: the development of novel classes of quinuclidine derivatives acting as M 3 -receptor antagonists, 108 amongst other novel derivatives of tolterodine itself. 109 The related compound, fesoterodine (Fig. 27), is the phenolic ester of tolterodine as well as being its ArCH 3 -oxidised variant; 5-hydroxymethyl tolterodine is the active metabolite, suggesting that fesoterodine acts as a prodrug of 5-hydroxymethyl tolterodine.…”

Section: Inhibitor Of Human Fatty-acid Amide Hydrolasementioning

confidence: 99%