23981-47-7Relevant articles and documents
A photophysical and photochemical study of 6-methoxy-2-naphthylacetic acid, the major metabolite of the phototoxic nonsteroidal antiinflammatory drug nabumetone
Bosca,Canudas,Marin,Miranda
, p. 173 - 177 (2000)
Nabumetone is a phototoxic nonsteroidal antiinflammatory drug used for the treatment of osteoarthritis. However, nabumetone is considered a prodrug with its metabolite 6-methoxy-2-naphthylacetic acid the active form. Photophysical and photochemical studies on this metabolite have been undertaken. It undergoes photodecarboxylation in aerated aqueous and organic solvents. In addition to the accepted photodegradation pathway for related molecules, a new mechanism that implies generation of the naphthalene radical cation from the excited singlet and addition of O2 prior to the decarboxylation process has been demonstrated. Evidence for the involvement of the excited singlet state in this mechanism have been obtained by steady-state and time-resolved fluorescence experiments. The fluorescence quenching by O2 and the shorter singlet lifetime in aerated solvents support this assignment. Laser flash photolysis also supports this mechanism by showing the noninvolvement of the triplet in the formation of the naphthalene radical cation. Finally, the well-known electron acceptor CCl4 acts as an efficient singlet quencher, enhancing the route leading to the radical cation, preventing intersystem crossing to the triplet and thus resulting in a dramatic increase in the yield of 6-methoxy-2-naphthaldehyde, the major oxidative decarboxylation product; this constitutes unambiguous proof in favor of the new mechanistic proposals.
Baeyer-Villiger Monooxygenase FMO5 as Entry Point in Drug Metabolism
Fiorentini, Filippo,Romero, Elvira,Fraaije, Marco W.,Faber, Kurt,Hall, Mélanie,Mattevi, Andrea
, p. 2379 - 2387 (2017)
Flavin-containing monooxygenases (FMOs) are emerging as effective players in oxidative drug metabolism. Until recently, the functions of the five human FMO isoforms were mostly linked to their capability of oxygenating molecules containing soft N- and S-nucleophiles. However, the human FMO isoform 5 was recently shown to feature an atypical activity as Baeyer-Villiger monooxygenase. With the aim of evaluating such an alternative entry point in the metabolism of active pharmaceutical ingredients, we selected and tested drug molecules bearing a carbonyl group on an aliphatic chain. Nabumetone and pentoxifylline, two widely used pharmaceuticals, were thereby demonstrated to be efficiently oxidized in vitro by FMO5 to the corresponding acetate esters with high selectivity. The proposed pathways explain the formation of a predominant plasma metabolite of pentoxifylline as well as the crucial transformation of the pro-drug nabumetone into the pharmacologically active compound. Using the recombinant enzyme, the ester derivatives of both drugs were obtained in milligram amounts, purified, and fully characterized. This protocol can potentially be extended to other FMO5 candidate substrates as it represents an effective and robust bench-ready platform applicable to API screening and metabolite synthesis.
Synthesis and evaluation of some gastrointestinal sparing anti-inflammatory aminoethyl ester derivatives of naphthalene-based NSAIDs
Halen, Parmeshwari K.,Raval, Manisha K.,Chagti, Kewal K.,Giridhar, Rajani,Yadav, Mange R.
, p. 88 - 94 (2007)
To overcome the local gastric toxicity associated with use of, common non-steroidal anti-inflammatory drugs (NSAIDs), some aminoalcohol esters of NSAIDs bearing structural resemblance to the aminoalcohol ester class of anticholinergics were specially designed and synthesized. Besides blocking the acidic carboxyl group to overcome the local gastric irritation, the anticholinergic activity was incorporated with the expected advantage of reducing the gastric toxicity by decreasing gastric acid secretions and motility. Derivatives of naproxen and 6-methoxy-2-napthylacetic acid (6-MNA) were synthesized. The hydrolysis studies in buffers revealed the majority of the compounds to be sufficiently stable with a high enzymatic susceptibility in 80% human serum. Most of the derivatives exhibited a fairly good anticholinergic action against acetylcholine with a significant reduction in ulcerogenicity while retaining the anti-inflammatory potency of the parent drug. The combination of anti-inflammatory and anticholinergic activities, with a simultaneous reduction of the acidic character, may lead to development of therapeutically better compounds than the parent NSAIDs for long-term oral anti-inflammatory therapy.
Oxidation of Alkynyl Boronates to Carboxylic Acids, Esters, and Amides
Li, Chenchen,Li, Ruoling,Zhang, Bing,Zhao, Pei,Zhao, Wanxiang
supporting information, p. 10913 - 10917 (2020/05/25)
A general efficient protocol was developed for the synthesis of carboxylic acids, esters, and amides through oxidation of alkynyl boronates, generated directly from terminal alkynes. This protocol represents the first example of C(sp)?B bond oxidation. This approach displays a broad substrate scope, including aryl and alkyl alkynes, and exhibits excellent functional group tolerance. Water, primary and secondary alcohols, and amines are suitable nucleophiles for this transformation. Notably, amino acids and peptides can be used as nucleophiles, providing an efficient method for the synthesis and modification of peptides. The practicability of this methodology was further highlighted by the preparation of pharmaceutical molecules.
N-{[2-(PIPERIDIN-1-YL)PHENYL](PHENYL)METHYL}-2-(3-OXO-3,4-DIHYDRO-2H-1,4-BENZOXA ZIN-7-YL)ACETAMIDE DERIVATIVES AND RELATED COMPOUNDS AS ROR-GAMMA MODULATORS FOR TREATING AUTOIMMUNE DISEASES
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Page/Page column 68; 96, (2018/08/20)
The present invention provides e.g. N-{[2-(piperidin-1-yl)phenyl] (phenyl)methyl}-2-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)acetamide derivatives and related compounds as ROR-gamma modulators for treating e.g. autoimmune diseases, autoimmune-related diseases, inflammatory diseases, metabolic diseases, fibrotic diseases or cholestatic diseases, such as e.g. arthitis and asthma.
COMPOSITIONS AND METHODS FOR SUBSTRATE-SELECTIVE INHIBITION OF ENDOCANNABINOID OXYGENATION
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Page/Page column 57; 59, (2014/02/15)
Methods for selectively inhibiting endocannabinoid oxygenation but not arachidonic acid oxygenation. In some embodiments, the methods include contacting a COX-2 polypeptide with an effective amount of a substrate-selective COX-2 inhibitor. Also provided are methods for elevating a local endogenous cannabinoid concentrations; methods of reducing depletion of an endogenous cannabinoid; methods for inducing analgesia; methods of providing anxiolytic therapy; methods for providing anti-depressant therapy; and compositions for performing the disclosed methods.
Substrate-selective inhibition of cyclooxygenase-2: Development and evaluation of achiral profen probes
Windsor, Matthew A.,Hermanson, Daniel J.,Kingsley, Philip J.,Xu, Shu,Crews, Brenda C.,Ho, Winnie,Keenan, Catherine M.,Banerjee, Surajit,Sharkey, Keith A.,Marnett, Lawrence J.
, p. 759 - 763 (2012/10/29)
Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid and the endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamide (AEA). We recently reported that (R)-profens selectively inhibit endocannabinoid oxygenation but not arachidonic acid oxygenation. In this work, we synthesized achiral derivatives of five profen scaffolds and evaluated them for substrate-selective inhibition using in vitro and cellular assays. The size of the substituents dictated the inhibitory strength of the analogs, with smaller substituents enabling greater potency but less selectivity. Inhibitors based on the flurbiprofen scaffold possessed the greatest potency and selectivity, with desmethylflurbiprofen (3a) exhibiting an IC50 of 0.11 μM for inhibition of 2-AG oxygenation. The crystal structure of desmethylflurbiprofen complexed to mCOX-2 demonstrated a similar binding mode to other profens. Desmethylflurbiprofen exhibited a half-life in mice comparable to that of ibuprofen. The data presented suggest that achiral profens can act as lead molecules toward in vivo probes of substrate-selective COX-2 inhibition.
Palladium-catalyzed intramolecular decarboxylative allylic arylation of α-aryl-γ-methylidene-δ-valerolactones
Shintani, Ryo,Tsuji, Takaoki,Park, Soyoung,Hayashi, Tamio
supporting information; experimental part, p. 1697 - 1699 (2010/07/07)
A palladium-catalyzed intramolecular decarboxylative cyclization of α-aryl-γ-methylidene-δ-valerolactones, followed by olefin isomerization, has been developed to give fused polycyclic aromatic compounds under mild conditions. The process described here can be regarded as a formal decarboxylative allylic arylation without using a pre-formed organometallic nucleophile. The reaction can be conducted on a gram scale and the products thus obtained are further derivatized with ease.
Phase-transfer catalyzed asymmetric arylacetate alkylation
Andrus, Merritt B.,Harper, Kaid C.,Christiansen, Michael A.,Binkley, Meisha A.
supporting information; experimental part, p. 4541 - 4544 (2009/12/03)
Phenethyl arylacetates are alkylated under phase-transfer conditions with cinchona catalysts with alkyl halides in high yield with excellent enantioselectivity (84-99% ee) following recrystallization. Cinchonidine (CD) derived catalyst gave the (R)-product and cinchonine (CN) catalyst produced the (S)-product. The phenethyl (PE) ester group is removed, using ammonium formate and catalytic Pd/C, to give alkylated carboxylic acid products in high selectivity. The utility of the approach is demonstrated by a direct synthesis of (S)-naproxen.
Syntheses of (R,S)-naproxen and its 6-O-desmethylated metabolite labelled with 2H
Fontana,Venegoni
, p. 239 - 241 (2008/12/20)
Naproxen, a well-known non-steroidal anti-inflammatory drug, and its 6-O-desmethylated metabolite have been labelled with 2H. (R,S)-Naproxen 7 labelled with 2H was obtained in five steps using the commercially available [2H3]iodomethane 5 as the stable labelled reagent. The demethylation of 7 using 48% HBr in 1-butyl-3-methylimidazolium tetrafluoborate gave the corresponding 2H-labelled 6-O-desmethylated metabolite 8. Copyright
