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Retinoids in Antiaging Therapy
Published in Ayse Serap Karadag, Berna Aksoy, Lawrence Charles Parish, Retinoids in Dermatology, 2019
Zehra Aşiran Serdar, Ezgi Aktaş Karabay
Tazarotene, an acetylenic retinoid, is used mainly in the treatment of psoriasis and acne. Tazarotene is a prodrug that is rapidly metabolized to its active form, tazarotenic acid. Although tazarotene is a member of the retinoid family, it presents a different receptor selectivity pattern from tretinoin. Tretinoin directly activates all RAR subtypes, while it indirectly stimulates RXRs; tazarotenic acid selectively binds to RAR-β and RAR-γ but not RXRs (1).
Radiolabeled Enzyme Inhibitors
Published in William C. Eckelman, Lelio G. Colombetti, Receptor-Binding Radiotracers, 2019
The acetylenic-type inhibitors could, in theory at least, be used to irreversibly bind to fatty acid dehydrogenases. In the heart two enzymes, Acyl-CoA dehydrogenase and enoyl-CoA isomerase, could potentially generate a reactive aliène during β-oxidation. In the radiopharmaceutical arena, the approach could logically be applied to radiolabeled fatty acids such as 123I-ω-iodoheptadecanoic acid and 123I-ω-iodohexadecenoic acid, compounds that are being evaluated as clinical myocardial imaging agents.41,42 Like the essential fatty acids, palmitic and oleic acids, the ω-iodofatty acids are rapidly and efficiently extracted by the myocardium.43,44 Although definitive evidence is lacking, the ω-iodofatty acids seemingly undergo β-oxidation in the heart. Their myocardial T1/2 is short and blood radioactivity levels are moderately high due to the presence of free radioiodide. The free radioiodide in the blood is most likely due to deiodination of the labile end products of β-oxidation: iodopropionate and iodoacetate.
Disposition and Metabolism of Drugs of Dependence
Published in S.J. Mulé, Henry Brill, Chemical and Biological Aspects of Drug Dependence, 2019
A method for the estimation of this drug in biological materials has been described and studies with isolated tissues have shown that liver, kidney, and to a smaller extent, brain can inactivate this drug.434 Studies on its metabolic disposition435 in dog and man have suggested that in the dog, 17 to 29% of the drug is metabolized to a glucuronide conjugate lacking the acetylenic group. Fate of the remaining drug was unknown. Orally administered meparfynol appears to be adequately absorbed from the gastrointestinal tract; however, the metabolism436 in human patients is slow and the drug can be detected in patients 48 hours after its administration. It is distributed in total body water and reaches somewhat higher concentrations in liver and depot fats than in other tissues. Small amounts of unchanged drug are eliminated in breath and in urine.437
Induced polygenic variations through
Published in International Journal of Radiation Biology, 2019
Raj Kishori Lal, Chandan Singh Chanotiya, Ved Ram Singh, Sunita Singh Dhawan, Pankhuri Gupta, Shama Shukla, Anand Mishra
In nutshell, after screening in IET, BST, and PST field trials, one promising mutant SELM-1 was isolated. This novel mutant SELM-1 is very promising for high flower and essential oil yield rich in acetylenic compound (2Z,8Z)-matricaria acid methyl ester (76–80%) with unique fruity notes and red essential oil valued for perfumery and pharmaceutical industries (Figure 3(B)). This mutant chemotype has the production potential of 7.00–7.50 q ha−1 dry flowers and 6.00–6.50 kg ha−1 essential oil yield. The acetylenic compound (2Z,8Z)-matricaria acid methyl ester is effective against hyperpigmentation of human skin (Luo et al. 2009) to be useful in cosmetic and pharmaceutical industries. This mutant genotype SELM-1 recently released as variety CIM-Ujjwala for commercial cultivation for large scale. The distinct morphological features of variety CIM-Ujjwala are presented in Table 6. This novel mutant chemotype would provide a high remunerative return to the growers and essential oil, perfumery and pharmaceutical industries.
Acetylenes: cytochrome P450 oxidation and mechanism-based enzyme inactivation
Published in Drug Metabolism Reviews, 2019
The reactions catalyzed by cytochrome P450, with some exceptions, fall into three classes: (i) hydroxylations in which an oxygen is inserted between a hydrogen and a heavier element, usually carbon or nitrogen; (ii) heteroatom oxidations, in which the oxygen atom is added to the free electron pair of a heteroatom, usually nitrogen or sulfur; and (iii) oxidation of double, triple, or aromatic π-bonds. This review focuses exclusively on the oxidation of carbon–carbon triple bonds (i.e. acetylenic groups). The oxidation of acetylenes resembles in some, but not all respects the oxidation of olefinic bonds. The oxidation of triple bonds has appeared in general reviews on the mechanism of cytochrome P450 enzymes (e.g. Ortiz de Montellano 2015) and the mechanism-based inactivation of cytochrome P450 enzymes (e.g. Correia and Hollenberg 2015), but the last review dealing extensively with the oxidation of acetylenes was published more than 30 years ago (Ortiz de Montellano 1985). This review updates our understanding of the oxidation of acetylenes in the light of the information obtained in the quarter of a century since that last review. The discussion of the formation of metabolites and the inactivation of cytochrome P450 enzymes includes a critical reevaluation of the putative role of oxirenes as reaction intermediates, the oxidation of disubstituted triple bonds, and the nature of ‘reversible’ inhibitory complexes.
Evaluation of WO2014121383 A1: a process for preparation of rufinamide and intermediates
Published in Expert Opinion on Therapeutic Patents, 2019
Barnali Maiti, Balamurali M M, Kaushik Chanda
The aim of this patent evaluation is to point out recent advances made in the field of synthesis of rufinamide which will encourage scientists further to design and develop new synthetic routes to rufinamide. The invention in this patent application relates to the synthesis of rufinamide 1 and its intermediates using activated acetylenic esters as dipolarophile for the treatment ofLGS. At present most of the synthetic methods for the synthesis of rufinamide involved the use of costly 2-chloroacrylonitrile, propiolic acid, and esters which is time consuming, low yields and often coupled with the problem of regioselectivity. In an effort to attain the regioselective synthesis of rufinamide, several Cu(I) catalyzed synthetic routes have been developed. In this patent evaluation, a large number of activated acetylenic esters were prepared from N-hydroxy succinimide, N-hydroxyphthalimide, 1-hydroxy benzotriazole, or 4-nitro phenol. Further the acetylenic esters were investigated for Cu(I) catalyzed 1,3-dipolar cycloaddition reaction to obtain the rufinamide in good yields. Further the patent also synthesized the rufinamide through in-situ generated activated acetylenic esters in one-pot methodology which saves the time and provided efficient yields. This patent provides good examples of using activated acetylenic esters as dipolarophile for the synthesis of rufinamide using regioselective Cu catalyzed cycloaddtion of dipolarophiles with 2,6-difluro benzyl azide in three steps. These activated acetylenic esters may be good lead for the discovery of more potent anitiepileptic drugs for the treatment of neurological disorder. The synthesized activated acetylenic esters are regarded as useful synthons. Moreover, these activated acetylenic esters can be useful for amide and ester synthesis with amines or alcohols, acylation reactions, and five-member heterocyclic molecule syntheses.