- Cytochrome P4502D and -2C enzymes catalyze the oxidative N-demethylation of the Parkinsonism-inducing substance 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in rat liver microsomes
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We have examined the oxidative N-demethylation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a Parkinsonism-inducing neurotoxin, in liver microsomes from adult Wistar and Dark Agouti (DA) rats. The oxidation of MPTP to 4-phenyl-1,2,3,6-tetrahydropyridine (PTP) in these preparations required NADPH as a cofactor and was significantly inhibited by SKF 525-A (2 mM). MPTP N-demethylation exhibited biphasic kinetics, consistent with two enzymes, a low Km system (Km1, 10.0 ± 2.2 μM; Vmax1, 0.048 ± 0.009 nmol/(min·mg of protein)) and a high Km system (Km2, 1180 ± 91 μM; Vmax2, 4.80 ± 0.75 nmol/(min·mg of protein)). We thus employed two substrate concentrations, 5 μM and 5 mM, for the low and high Km system, respectively, to assay enzyme activity in subsequent experiments. The oxidation activity was significantly decreased by pretreatment of rats with phenobarbital and β-naphthoflavone. Furthermore, marked strain (Wistar > DA) and sex (male > female) differences were observed at low (5 μM) and high (5 mM) substrate concentrations, respectively. Reconstitution experiments with cytochrome P450BTL, which belongs to the P4502D subfamily, and P450ml (P4502C11) demonstrated that MPTP N-demethylase occurs at concentrations of 5 μM and 5 mM. At 5 mM the male-specific P450ml showed a remarkably high activity, over 400-fold that of P450BTL. Polyclonal antibodies against P450BTL and P450ml effectively suppressed the activity at the low (5 μM) and the high (5 mM) substrate concentrations, respectively. These results suggest that, in the microsomal preparations used, MPTP N-demethylation is mainly mediated by P4502D enzyme(s) at lower substrate concentrations and by P4502C11 at higher substrate concentrations.
- Narimatsu, Shizuo,Tachibana, Masaya,Masubuchi, Yasuhiro,Suzuki, Tokuji
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- Rat liver microsomal enzyme catalyzed oxidation of 4-phenyl-trans-1-(2-phenylcyclopropyl)-1,2,3,6-tetrahydropyridine
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As part of our ongoing studies to characterize the catalytic pathway(s) for the monoamide oxidase and cytochrome P450 catalyzed oxidations of 1,4-disubstituted 1,2,3,6-tetrahydropyridinyl derivatives, we have examined the metabolic fate of 4-phenyl-trans-1-(2-phenylcyclopropyl)-1,2,3,6-tetrahydropyiridine in NADPH supplemented rat liver microsomes. Three metabolic pathways have been identified: (1) allylic ring α-carbon oxidation to yield the dihydropyridinium species, (2) nitrogen oxidation to yield the N-oxide and (3) N-dealkylation to yield 4-phenyl-1,2,3,6-tetrahydropyridine and cinnamaldehyde. A possible mechanism to account for the formation of cinnamaldehyde involves an initial single electron transfer from the nitrogen lone pair to the iron oxo system Fe+3(O) to form the corresponding cyclopropylaminyl radical cation that will be processed further to the final products. The reaction pathway leading to the dihydropyridinium metabolite may also proceed via the same radical cation intermediate but direct experimental evidence to this effect remains to be obtained. Copyright
- Kuttab, Simon,Shang, Jackie,Castagnoli Jr., Neal
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- B(C6F5)3-Catalyzed Cascade Reduction of Pyridines
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B(C6F5)3 has been found to be an effective catalyst for reduction of pyridines and other electron-deficient N-heteroarenes with hydrosilanes (or hydroboranes) and amines as the reducing reagents. The success of this development hinges upon the realization of a cascade process of dearomative hydrosilylation (or hydroboration) and transfer hydrogenation. The broad functional-group tolerance (e.g. ketone, ester, unactivated olefins, nitro, nitrile, heterocycles, etc.) implies high practical utility.
- Liu, Zhi-Yun,Wen, Zhi-Hui,Wang, Xiao-Chen
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supporting information
p. 5817 - 5820
(2017/05/12)
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- The use of organolithium reagents for the synthesis of 4-aryl-2-phenylpyridines and their corresponding iridium(III) complexes
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A versatile palladium-free route for the synthesis of 4-aryl-substituted phenylpyridines (ppy), starting from tert-butyl 4-oxopiperidine-1-carboxylate, is reported. Reaction with an aryllithium, followed by trifluoroacetic acid dehydration/deprotection and oxidation with 2-iodoylbenzoic acid and finally phenylation, gave 4 ligands (L1-4H): 2,4-diphenylpyridine, 4-(4-methoxyphenyl)-2-phenylpyridine, 2-phenyl-4-(o-tolyl)pyridine and 4-mesityl-2-phenylpyridine. These ligands were coordinated to iridium to give the corresponding Ir(L)2(A) complexes (Ir1-7), where A = ancillary ligand acetylacetate or 2-picolinate. This was used to demonstrate that, through a combination of ancillary ligand choice and torsional twisting between the 4-aryl substituents of the ppy ligands, it is possible to tune the phosphorescent emission of the complexes in the range 502-560 nm.
- Davidson, Ross,Hsu, Yu-Ting,Batchelor, Thomas,Yufit, Dmitry,Beeby, Andrew
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p. 11496 - 11507
(2016/07/26)
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- Synthesis and biological evaluation of 1-(isoxazol-5-ylmethylaminoethyl)-4- phenyl tetrahydropyridine and piperidine derivatives as potent T-type calcium channel blockers with antinociceptive effect in a neuropathic pain model
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New tetrahydropyridinyl and piperidinyl ethylamine derivatives were designed with hypothetical mapping on pharmacophore model generated from ligand-based virtual screening. The designed compounds were synthesized, and their inhibitory activities on T-type calcium channel were assayed using FDSS and patch-clamp assay. Among them, compounds 7b and 10b showed potent T-type calcium current blocking activity against Cav3.1 (α 1G) and Cav3.2 (α1H) channel simultaneously. With hERG and pharmacokinetics studies, compounds 7b and 10b were evaluated for the antinociceptive effect on rat model of neuropathic pain. They were significantly effective in decreasing the pain responses to mechanical and cold allodynia induced by spinal nerve ligation. These results suggest that modulation of α1G and α1H subtype T-type calcium channels may provide a promising approach for the treatment of neuropathic pain.
- Lee, Ju-Hyeon,Seo, Seon Hee,Lim, Eun Jeong,Cho, Nam-Chul,Nam, Ghilsoo,Kang, Soon Bang,Pae, Ae Nim,Jeong, Nakcheol,Keum, Gyochang
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p. 246 - 257
(2014/02/14)
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- Structure-activity relationship exploration of Kv1.3 blockers based on diphenoxylate
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Diphenoxylate, a well-known opioid agonist and anti-diarrhoeal agent, was recently found to block Kv1.3 potassium channels, which have been proposed as potential therapeutic targets for a range of autoimmune diseases. The molecular basis for this Kv1.3 blockade was assessed by the selective removal of functional groups from the structure of diphenoxylate as well as a number of other structural variations. Removal of the nitrile functional group and replacement of the C-4 piperidinyl substituents resulted in several compounds with submicromolar IC50 values.
- Nguyen, William,Howard, Brittany L.,Jenkins, David P.,Wulff, Heike,Thompson, Philip E.,Manallack, David T.
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supporting information
p. 7106 - 7109
(2013/01/15)
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- Design, synthesis, and evaluation of novel aryl-tetrahydropyridine PPARα/γ dual agonists
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Aryl-tetrahydropyridine derivatives were prepared and their PPARα/γ dual agonistic activities were evaluated. Among them, compound (S)-5b was identified as a potent PPARα/γ dual agonist with an EC50 of 1.73 and 0.64 μM in hPPARα and γ, respectively. In diabetic (db/db) mice, compound (S)-5b showed good glucose lowering efficacy and favorable pharmacokinetic properties.
- Kim, Eunkyung,Park, Chan Sun,Han, Taedong,Bae, Myung-Ho,Chong, Wonee,Lee, Choong Hyun,Shin, Young Ah,Ahn, Byung-Nak,Kim, Mi Kyung,Shin, Chang Yell,Son, Moon Ho,Kim, Jin Kwan,Moon, Ho Sang,Shim, Hyun Joo,Kim, Eun Jung,Kim, Soon Hoe,Lim, Joong In,Lee, Chun Ho
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scheme or table
p. 4993 - 4996
(2009/05/26)
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- METHODS AND COMPOSITIONS FOR TREATING AMYLOID-RELATED DISEASES
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Methods, compounds, pharmaceutical compositions and kits are described for treating or preventing amyloid-related disease.
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- Design and synthesis of orally active inhibitors of TNF synthesis as anti-rheumatoid arthritis drugs
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A novel series of TNF inhibitors was identified based on the screening of existing MMP inhibitor libraries. Further SAR optimization led to the discovery of a novel lead compound. Its synthesis, efficacy in experimental animal models, and pharmacokinetic
- Chen, Jian Jeffrey,Dewdney, Nolan,Lin, Xiaohong,Martin, Robert L.,Walker, Keith A. M.,Huang, Jane,Chu, Frances,Eugui, Elsie,Mirkovich, Anna,Kim, Yong,Sarma, Keshab,Arzeno, Humberto,Van Wart, Harold E.
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p. 3951 - 3954
(2007/10/03)
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- Piperidine derivatives having renin inhibiting activity
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Novel piperidine derivatives, their manufacture and use as medicaments, are disclosed. The invention is concerned with the novel piperidine derivatives of general formula I wherein R1, R2, R3, R4, Q, X, Z, m and n are as described herein.
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- 14-substituted marcfortines and derivatives useful as antiparasitic agents
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There are disclosed 14α-hydroxymarcfortine derivatives of the natural products marcfortine A, B, C, and D useful in the treatment and prevention of helminth and arthropod infections of animals and plants. The synthetic derivatives are of Formula (I). STR1
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- Marcfortine/paraherquamide derivatives useful as antiparasitic agents
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There are disclosed 18-thiomarcfortine derivatives of the natural products marcfortine A, B and C, C-18 thioparaherquamide and derivatives thereof, novel N-1 marcfortines A, B, and C and derivatives thereof, novel N-1 paraherquamide and derivatives thereof usefull in the treatment and prevention of helninth and arthropod infections of animals and plants. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Examiner Robert T. Bond whose telephone number is (703)308-4711. The examiner can normally be reached on Monday through Friday from 8:00 AM to 4:30 PM.
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- Quinoxalines and drugs prepared therefrom
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Quinoxaline-2,3-(1H,4H)-diones of the formula I STR1 and their tautomeric and enantiomeric forms and their physiologically tolerated salts, the variables R, R 1 and R 2 have the meanings specified in claim 1, and are useful for therapeutic treatment of neurodegenerative disorders, neurotoxic disturbances or as antiepileptics, antidepressants and anxiolytics; and drugs composed thereof.
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- Rat liver microsomal enzyme catalyzed oxidation of 1-cyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine
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NADPH supplemented rat liver microsomal enzyme preparations catalyze the conversion of 1-cyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine to the p-hydroxyphenyl (low yield), descyclopropyl (high yield) and 2,3-dihydropyridinium and, subsequently, pyridinium (intermediary yield) metabolites. When the methine proton of the cyclopropyl group was replaced with a deuteron, a normal deuterium isotope effect (1.4) was observed on the formation of the decyclopropylated metabolite and an inverse isotope effect (0.6) on the dihydropyridinium metabolite. A larger deuterium isotope effect (3.6) was observed on the ring α-carbon oxidation pathway with the 2,2,6,6-d4 analogue as substrate. These results and the observation that the ratios of the rates of these two α-carbon oxidation pathways are independent of initial substrate concentrations suggest that both pathways are catalyzed by the same active site of one form of P450. These transformations are discussed in terms of metabolic pathways that have been proposed for the cytochrome P450 catalyzed α-carbon oxidation of amines. Copyright (C) 1998 Elsevier Science Ltd.
- Zhao, Zhiyang,Mabic, Stephane,Kuttab, Simon,Franot, Christelle,Castagnoli, Kay,Castagnoli Jr., Neal
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p. 2531 - 2539
(2007/10/03)
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- Antiatherosclerotic and antithrombotic 1-benzopyran-4-ones and 2-amino-1,3-benzoxazine-4-ones
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This invention relates to compounds of Formula I STR1 which are useful in association with a pharmaceutical carrier as antiatherosclerotic agents. In addition, various compounds of Formula I are useful inhibitors of cell proliferation.
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- Antiatherosclerotic and antithrombotic 2-amino-6-phenyl-4H-pyran-4-ones
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This invention relates to compounds of Formula I STR1 which are useful as antiatherosclerotic agents and inhibitors of cell proliferation for the treatment of proliferative diseases. In addition, various compounds of Formula I are useful inhibitors of platelet aggregation.
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- Isolation and Structure Elucidation of the By-Product Formed in the Aminomethylation of α-Methylstyrene
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Aminomethylation of α-Methylstyrene (1) leads to 1,2,3,6-tetrahydro-4-phenylpyridine (3) as main product, together with a significant amount of a previously unknown by-product.The N-methyl, O-acetyl-N-methyl, N,O-diacetyl, N-(4-nitrobenzoyl), and (via N -> O acyl-migration) O-(4-nitrobenzoyl) derivatives of the by-product were synthesized.By aromatization of the heteroring, 4-phenyl-3-pyridinemethanol (8a) was obtained.According to these derivatives and their IR, 1H and 13C NMR spectra, the by-product is 1,2,3,6-tetrahydro-4-phenyl-3-pyridine-methanol (4a).
- Sohar, Pal,Lazar, Janos,Bernath, Gabor
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p. 551 - 559
(2007/10/02)
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- Treatment of atherosclerosis with khellin-related furochromones
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The present specification relates to the antiatherosclerotic use of khellin and related furochromones, and further provides novel antiatherogenic furochromones.
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- Antiatherosclerotic furochromones
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The present specification relates to the antiatherosclerotic use of khellin and related furochromones, and further provides novel antiatherogenic furochromones.
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