- Synthesis of stable isotopically labelled versions of Lamotrigine and its methylated metabolite
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Lamotrigine is a sodium channel antagonist used for the treatment of epilepsy. Synthesis of stable isotopically labelled (SIL) [M + 7] versions of Lamotrigine (1) and its N-methylated metabolite (2) are described. The routes to prepare these compounds used [M + 5] labelled [13C, 15N4]-aminoguanidine (obtained from labelled thiourea). The overall yield for the metabolite (2) was 34% from [M + 3] labelled [13C, 15N2]-thiourea. Copyright
- Manning, Calvin O.,Wadsworth, Alan H.,Fellows, Ian
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- Remarkably Efficient Iridium Catalysts for Directed C(sp2)-H and C(sp3)-H Borylation of Diverse Classes of Substrates
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Here we describe the discovery of a new class of C-H borylation catalysts and their use for regioselective C-H borylation of aromatic, heteroaromatic, and aliphatic systems. The new catalysts have Ir-C(thienyl) or Ir-C(furyl) anionic ligands instead of the diamine-type neutral chelating ligands used in the standard C-H borylation conditions. It is reported that the employment of these newly discovered catalysts show excellent reactivity and ortho-selectivity for diverse classes of aromatic substrates with high isolated yields. Moreover, the catalysts proved to be efficient for a wide number of aliphatic substrates for selective C(sp3)-H bond borylations. Heterocyclic molecules are selectively borylated using the inherently elevated reactivity of the C-H bonds. A number of late-stage C-H functionalization have been described using the same catalysts. Furthermore, we show that one of the catalysts could be used even in open air for the C(sp2)-H and C(sp3)-H borylations enabling the method more general. Preliminary mechanistic studies suggest that the active catalytic intermediate is the Ir(bis)boryl complex, and the attached ligand acts as bidentate ligand. Collectively, this study underlines the discovery of new class of C-H borylation catalysts that should find wide application in the context of C-H functionalization chemistry.
- Chattopadhyay, Buddhadeb,Hassan, Mirja Md Mahamudul,Hoque, Md Emdadul
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supporting information
p. 5022 - 5037
(2021/05/04)
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- Synthesis and anti-rheumatoid arthritis activities of 3-(4-aminophenyl)-coumarin derivatives
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Rheumatoid arthritis is a chronic systemic disease characterised by an unknown aetiology of inflammatory synovitis. A large number of studies have shown that synoviocytes show tumour-like dysplasia in the pathological process of RA, and the changes in the expression of related cytokines are closely related to the pathogenesis of RA. In this thesis, a series of novel 3-(4-aminophenyl) coumarins containing different substituents were synthesised to find new coumarin anti-inflammatory drugs for the treatment of rheumatoid arthritis. The results of preliminary activity screening showed that compound 5e had the strongest inhibitory activity on the proliferation of fibroid synovial cells, and it also had inhibitory effect on RA-related cytokines IL-1, IL-6, and TNF-α. The preliminary mechanism study showed that compound 5e could inhibit the activation of NF-κB and MAPKs signal pathway. The anti-inflammatory activity of compound 5ein?vivo was further determined in the rat joint inflammation model.
- Miao, Yuhang,Yang, Jie,Yun, Yinling,Sun, Jie,Wang, Xiaojing
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p. 450 - 461
(2021/02/19)
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- Base-promoted Lewis acid catalyzed synthesis of quinazoline derivatives
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A one-pot protocol has been developed for the synthesis of quinazolinones from amide-oxazolines with TsCl via a cyclic 1,3-azaoxonium intermediate and 6π electron cyclization in the presence of a Lewis acid and base. The process is operationally simple and has a broad substrate scope. This method provides a unique strategy for the construction of quinazolinones.
- Cui, Xin-Feng,Hu, Fang-Peng,Huang, Guo-Sheng,Lu, Guo-Qiang
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supporting information
p. 4376 - 4380
(2020/10/20)
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- Synthesis and biological evaluation of 3–(4-aminophenyl)-coumarin derivatives as potential anti-Alzheimer’s disease agents
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The work is focused on the design of drugs that prevent and treat Alzheimer’s disease (AD) and its complications. A series of 3–(4-aminophenyl)-coumarin derivatives designed, synthesised, fully characterised and evaluated in vitro/vivo. The biological assay experiments showed that some compounds displayed a clearly selective inhibition for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among all compounds, compound 4m exhibited the highest AChE inhibition with an IC50 value of 0.091 ± 0.011 μM and compound 4k exhibited the highest BuChE inhibition with an IC50 value of 0.559 ± 0.017 μM. A zebrafish behaviour analyser (Zebrobox) was used to determine the behavioural effects of the active compound on the movement distance of the aluminium chloride-induced zebrafish. Compound 4m offered a potential drug design concept for the development of therapeutic or preventive agents for AD and its complications.
- Hu, Yu-Heng,Yang, Jie,Zhang, Yun,Liu, Ke-Chun,Liu, Teng,Sun, Jie,Wang, Xiao-Jing
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p. 1083 - 1092
(2019/06/06)
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- An Evaluation of Multiple Catalytic Systems for the Cyanation of 2,3-Dichlorobenzoyl Chloride: Application to the Synthesis of Lamotrigine
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2,3-Dichlorobenzoyl cyanide is a key intermediate in the synthesis of Lamotrigine. An assessment of various catalytic systems for the cyanation of 2,3-dichlorobenzoyl chloride with cyanide salts is described. High-throughput experimentation identified many conditions for effecting the requisite chemistry, including amine bases and phase-transfer catalysts, as well as catalyst-free conditions utilizing acetonitrile as a polar cosolvent. A novel catalyst, CuBr2, was identified by consideration of the possible oxidation of Cu(I) during high-throughput screening experimentation. CuCN was found to be the best cyanide source for achieving clean conversion; however, the solubility of CuCN was the major factor limiting reaction rate under many conditions. Improving CuCN solubility by using acetonitrile as solvent enhanced the reaction rate even in the absence of the catalysts tested but significantly complicated isolation of the product. With no acetonitrile cosolvent, phase-transfer catalysts such as tetrabutylammonium bromide (TBABr) are effective; however, use of TBABr led to inconsistent reaction profiles from run-to-run, due to an unexpected clumping of the CuCN solid. Switching to cetyltrimethylammonium bromide (CTAB) alleviated this clumping behavior, leading to consistent reactivity. This CTAB-catalyzed process was scaled up, giving 560 kg of 2,3-dichlorobenzoyl cyanide in 77% isolated yield.
- Leitch, David C.,John, Matthew P.,Slavin, Paul A.,Searle, Andrew D.
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p. 1815 - 1821
(2017/11/24)
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- Design, synthesis and fungicidal activity of N-substituted benzoyl-1,2,3,4-tetrahydroquinolyl-1-carboxamide
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To find a new lead compound with high biological activity, a series of N-substituted benzoyl-1,2,3,4-tetrahydroquinolyl-1-carboxamide were designed using linking active substructures method. The target compounds were synthesized from substituted benzoic acid by four steps and their structures were confirmed by 1H NMR, IR spectrum and elemental analysis. The in vitro bioassay results indicated that some target compounds exhibited excellent fungicidal activities, and the position of the substituents played an important role in fungicidal activities. Especially, compound 5n, exhibited better fungicidal activities than the commercial fungicide flutolanil against two tested fungi Valsa Mali and Sclerotinia sclerotiorum, with EC50 values of 3.44 and 2.63 mg/L, respectively. And it also displayed good in vivo fungicidal activity against S. sclerotiorum with the EC50 value of 29.52 mg/L.
- Lei, Peng,Xu, Yan,Du, Juan,Yang, Xin-Ling,Yuan, Hui-Zhu,Xu, Gao-Fei,Ling, Yun
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supporting information
p. 2544 - 2546
(2016/07/07)
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- Improved synthesis process for lamotrigine
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The invention discloses an improved synthesis process for lamotrigine. The process comprises the following steps: (1) synthesizing 2,3-dichlorobenzoyl cyanide: adding 2,3-dichlorobenzoic acid and thionyl chloride into a reactor, carrying out depressurized evaporating to remove thionyl chloride after a reaction is completed, adding cuprous cyanide into the reactor, and filtering out solids after a reaction is completed, so as to obtain a 2,3-dichlorobenzoyl cyanide solution; (2) preparing a condensate: adding aminoguanidine carbonate and an entrainer into a reactor, dropwise adding concentrated sulfuric acid, distilling off the entrainer and water, carrying out suction filtration, enabling solids to enter a reaction bottle, carrying out depressurized pumping, then, adding the 2,3-dichlorobenzoyl cyanide solution obtained in the step (1) into the reaction bottle, cooling the reaction bottle to room temperature after a reaction is completed, and carrying out suction filtration, so as to obtain the condensate; and (3) preparing cyclics: adding liquid alkali into the condensate obtained in the step (2), and carrying out crystallizing, filtering, washing and baking after a reaction, thereby obtaining the lamotrigine. According to the improved synthesis process for the lamotrigine, the quality and yield of the product, i.e., the lamotrigine can be remarkably increased, and the yield reaches 90% or more.
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Paragraph 0031
(2017/07/21)
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- Regioselective synthesis of 1-substituted indazole-3-carboxylic acids
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In this article, we study the synthesis of 1-substituted indazole-3-carboxylic acids from 2-halobenzoic acids.
- Veerareddy, Arava,Gogireddy, Surendrareddy,Dubey
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p. 1311 - 1321
(2015/04/27)
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- Synthesis and SAR of 2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin- 5(9bH)-ones as 5-HT2C receptor agonists
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A series of 2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-ones is described, several examples of which exhibit potent 5-HT2C agonism with excellent selectivity over the closely related 5-HT2A and 5-HT2B receptors. Compounds such as 38 and 44 were shown to be effective in reducing food intake in an acute rat feeding model.
- Fevig, John M.,Feng, Jianxin,Rossi, Karen A.,Miller, Keith J.,Wu, Ginger,Hung, Chen-Pin,Ung, Thao,Malmstrom, Sarah E.,Zhang, Ge,Keim, William J.,Cullen, Mary Jane,Rohrbach, Kenneth W.,Qu, Qinling,Gan, Jinping,Pelleymounter, Mary Ann,Robl, Jeffrey A.
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p. 330 - 335
(2013/02/25)
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- Synthesis and evaluation of effective inhibitors of plant δ1-pyrroline-5-carboxylate reductase
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Analogues of previously studied phenyl-substituted aminomethylene- bisphosphonic acids were synthesized and evaluated as inhibitors of Arabidopsis thaliana δ1-pyrroline-5-carboxylate reductase. With the aim of improving their effectiveness, two main modifications were introduced into the inhibitory scaffold: the aminomethylenebisphosphonic moiety was replaced with a hydroxymethylenebisphosphonic group, and the length of the molecule was increased by replacing the methylene linker with an ethylidene chain. In addition, chlorine atoms in the phenyl ring were replaced with various other substituents. Most of the studied derivatives showed activity in the micromolar to millimolar range, with two of them being more effective than the lead compound, with concentrations inhibiting 50% of enzyme activity as low as 50 μM. Experimental evidence supporting the ability of these inhibitors to interfere with proline synthesis in vivo is also shown.
- Forlani, Giuseppe,Berlicki, Lukasz,Duo, Mattia,Dziedziola, Gabriela,Giberti, Samuele,Bertazzini, Michele,Kafarski, Pawel
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p. 6792 - 6798
(2013/08/23)
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- Discovery and characterization of AZD9272 and AZD6538 - Two novel mGluR5 negative allosteric modulators selected for clinical development
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AZD9272 and AZD6538 are two novel mGluR5 negative allosteric modulators selected for further clinical development. An initial high-throughput screening revealed leads with promising profiles, which were further optimized by minor, yet indispensable, structural modifications to bring forth these drug candidates. Advantageously, both compounds may be synthesized in as little as one step. Both are highly potent and selective for the human as well as the rat mGluR5 where they interact at the same binding site than MPEP. They are orally available, allow for long interval administration due to a high metabolic stability and long half-lives in rats and permeate the blood brain barrier to a high extent. AZD9272 has progressed into phase I clinical studies.
- Raboisson, Patrick,Breitholtz-Emanuelsson, Anna,Dahlloef, Henrik,Kers, Annika,Minidis, Alexander B. E.,Nordmark, Anna,Stroem, Peter,Terelius, Ylva,Wensbo, David,Edwards, Louise,Isaac, Methvin,Jarvie, Keith,Slassi, Abdelmalik,Wilson, Julie M.,Xin, Tao,Heaton, William L.,Sheehan, Susan M.,McLeod, Donald A.
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p. 6974 - 6979,6
(2020/09/02)
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- PYRROLIDINE SUBSTITUTED FLAVONES FOR THE TREATMENT OF INFLAMMATORY DISORDERS
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The present invention relates to the use of a compound of formula 1, a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, for the treatment of an inflammatory disorder. The invention further relates to a pharmaceutical composition comprising a compound of formula 1 and at least one pharmaceutically acceptable carrier, for use in the treatment of an inflammatory disorder. The invention also relates to a method for the treatment of an inflammatory disorder by administering a therapeutically effective amount of the compound of formula 1 to a subject in need thereof.
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Page/Page column 40-41
(2011/09/30)
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- Design, synthesis and structure-activity relationship studies of 6-phenyl-4,5-dihydro-3(2H)-pyridazinone derivatives as cardiotonic agents
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Based on our previous study, a variety of 12 novel 6-phenyl-4,5-dihydro- 3(2H)-pyridazinone derivatives were synthesized. The structures attributed to the compounds were elucidated using IR, 1H-NMR and mass spectra. The cardiotonic activities of these compounds were assessed by Straub's perfusion method and a clear cardiotonic effect was shown for compounds 1c (2,3-dichloro-N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl) benzamide), 1d (4-amino-3-methyl-N-(4-(4-methyl-6-oxo-1,4,5,6- tetrahydropyridazin-3-yl)phenyl)benzamide), 2a (3-methyl-4-nitro-N-(4-(6-oxo-1, 4,5,6-tetrahydropyridazin-3-yl)phenyl)benzamide) and 2d (4-amino-3-methyl -N-(4-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)benzamide) when compared to another 3(2H)-pyridazinone derivative, levosimendan (CAS 141505-33-1). The structure-activity relationships of the compounds were studied using the rough sets theory. ECV Editio Cantor Verlag.
- Wang, Teng,Dong, Ying,Wang, Li-Chen,Xiang, Bing-Ren,Chen, Zhen,Qu, Ling-Bo
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experimental part
p. 569 - 573
(2009/04/06)
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- Discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2, 1-a]isoindol-6(2H)-one, a selective, orally active agonist of the 5-HT 2C receptor
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Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currently marketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone- containing, selective 5-HT2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolone core was the identification of the appropriate substitution pattern and functional groups which led to the discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a] isoindol-6(2H)-one (58), a 5-HT2C agonist with > 300-fold functional selectivity over 5-HT2B and > 70-fold functional selectivity over 5-HT2A. Oral dosing of 58 reduced food intake in an acute rat feeding model, which could be completely reversed by a selective 5-HT2C antagonist and caused a reduction in body weight gain in a 4-day rat model.
- Wacker, Dean A.,Varnes, Jeffrey G.,Malmstrom, Sarah E.,Cao, Xueying,Hung, Chen-Pin,Ung, Thao,Wu, Ginger,Zhang, Ge,Zuvich, Eva,Thomas, Michael A.,Keim, William J.,Cullen, Mary Jane,Rohrbach, Kenneth W.,Qu, Qinling,Narayanan, Rangaraj,Rossi, Karen,Janovitz, Evan,Lehman-McKeeman, Lois,Malley, Mary F.,Devenny, James,Pelleymounter, Mary Ann,Miller, Keith J.,Robl, Jeffrey A.
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p. 1365 - 1379
(2007/10/03)
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- METHOD FOR PREPARING LAMOTRIGINE AND ITS INTERMEDIATE 2,3-DICHLOROBENZOYL CHLORIDE
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The invention relates to an improved method for preparing 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine, also commonly known as lamotrigine. The present invention also relates to a method for preparing the intermediate 2,3-dichlorobenzoyl chloride, which comprises the synthesis by photochlorination of 2,3-dichlorobenzotrichloride followed by hydrolysis thereof. Said 2,3-dichlorobenzoyl chloride intermediate is useful for preparing lamotrigine.
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Page/Page column 16
(2010/11/29)
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- Characterization of the histamine H4 receptor binding site. Part 1. Synthesis and pharmacological evaluation of dibenzodiazepine derivatives
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A series of dibenzodiazepine derivatives was synthesized to probe the binding site of the recently discovered histamine H4 receptor (H 4R). Optimization of the lead structure clozapine (2) resulted in (E)-7-chloro-11(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine (7j), a potent H4R agonist (H4R, pK, = 7.6). Pharmacological data suggests that the series of nonimidazole compounds can be used to describe the orthosteric binding site of the H4R because both 2 and 7j displace [3H]histamine in a competitive manner. Furthermore, it is demonstrated that the effects of 7j are competitively antagonized by the selective H4R antagonist JNJ 7777120 (1), indicating considerable overlap of their binding sites. On the basis of the derived structure-activity relationships and additional pharmacological results, a pharmacophore model was constructed, which will be the premise for the design of novel H4R ligands.
- Smits, Rogier A.,Lim, Herman D.,Stegink, Bart,Bakker, Remko A.,De Esch, Iwan J. P.,Leurs, Rob
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p. 4512 - 4516
(2007/10/03)
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- Synthesis and characterization of novel 6-fluoro-4-piperidinyl-1,2- benzisoxazole amides and 6-fluoro-chroman-2-carboxamides: Antimicrobial studies
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Novel derivatives of 6-fluoro-4-piperidinyl-1,2-benzisoxazole amides 4(I-VI) were obtained by the condensation of different acid chlorides with 6-fluoro-3-piperidin-4yl-benzo[d]isoxazole. Also, 6-fluoro-chroman-2- carboxamides 6(I-III) were synthesized by using nebulic acid chloride with different amines in presence of triethylamine as acid scavenger and dichloroethane as solvent. The synthesized compounds were characterized by IR, 1H NMR, and CHN analysis. These molecules were evaluated for their efficacy as antimicrobials in vitro by disc diffusion and microdilution method against pathogenic strains such as Bacillus substilis, Escherichia coli, Pseudomonas fluorescens, Xanthomonas campestris pvs, X. oryzae, Aspergillus niger, A. flavus, Fusarium oxysporum, Trichoderma species, F. monaliforme, and Penicillum species. Compounds 4I, 4IV, 4V, 6I, 6II and 6III showed better inhibitory activity than compared to standard drugs. Among these compounds, 4IV and 6III showed potent inhibitory activity against all the strains and found to be nonstrain dependent. The title compounds represent a novel class of potent antimicrobial agents.
- Priya,Basappa,Swamy, S. Nanjunda,Rangappa, Kanchugarakoppal S.
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p. 2623 - 2628
(2007/10/03)
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- LAMOTRIGINE MONOHYDRATE
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The invention relates to lamotrigine (3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine) monohydrate (Ia) and anhydrous lamotrigine, and a process for preparing the same. An improved process is provided for manufacturing the lamotrigine (I). The process comprises of reacting 2,3-dichlorobenzoyl cyanide (II) with aminoguanidine bicarbonate in aqueous mineral acid, optionally together with a water miscible organic solvent, at 30 - 80 °C to produce the 2-(2,3-dichlorophenyl)-2-(guanidinylamino)acetonitrile (Schiff base). The Schiff base is further cyclised in aqueous alcohol to produce pure lamotrigine of a pharmaceutically acceptable quality which on further drying at 45 - 50 °C under vacuum yields lamotrigine monohydrate, and/or on further drying at 100 - 110 °C yields anhydrous lamotrigine. The lamotrigine monohydrate or anhydrous lamotrigine thereby produced may then be brought into association with a pharmaceutically acceptable carrier for administration to a patient in need thereof.
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- Process for the preparation of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, commonly known as lamotrigine
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A process for the preparation of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3-5-diamine (lamotrigine) of the formula I: 2,3-Dichloronitrobenzene in C1-C6aliphatic alkanol is hydrogenated at 55-90 psi gas pressure using metal catalyst at 27-35° C. 2,3-Dichloroaniline is diazotised and cyano-de-diazonised with metal cyanide at 65-80° C. 2,3-Dichlorobenzonitrile is hydrolysed and 2,3-dichlorobenzoic acid is chlorinated at 55-130° C. Cyano-de-halogenation of 2,3-dichlorobenzoyl chloride is carried out with a metal cyanide and alkali metal iodide by refluxing in an aprotic solvent under an inert atmosphere. 2,3-Dichlorobenzoyl cyanide is condensed with aminoguanidine bicarbonate in an organic solvent in acidic conditions using catalyst at 90-125° C. followed by insitu cyclisation of the Schiff's base by refluxing in an aliphatic alkanol with base. Crude lamotrigine is purified.
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Page/Page column 8
(2010/01/31)
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- Structure-activity studies for a novel series of tricyclic substituted hexahydrobenz[e]isoindole α(1A) adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia (BPH)
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In search of a uroselective agent that exhibits a high level of selectivity for the α(1A) receptor, a novel series of tricyclic hexahydrobenz[e]isoindoles was synthesized. A generic pharmacophoric model was developed requiring the presence of a basic amine core and a fused heterocyclic side chain separated by an alkyl chain. It was shown that the 6- OMe substitution with R, R stereochemistry of the ring junction of the benz[e]isoindole and a two-carbon spacer chain were optimal. In contrast to the highly specific requirements for the benz[e]isoindole portion and linker chain, a wide variety of tricyclic fused heterocyclic attachments were tolerated with retention of potency and selectivity. In vitro functional assays for the α1 adrenoceptor subtypes were used to further characterize these compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity.
- Meyer, Michael D.,Altenbach, Robert J.,Basha, Fatima Z.,Carroll, William A.,Condon, Stephen,Elmore, Steven W.,Kerwin Jr., James F.,Sippy, Kevin B.,Tietje, Karin,Wendt, Michael D.,Hancock, Arthur A.,Brune, Michael E.,Buckner, Steven A.,Drizin, Irene
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p. 1586 - 1603
(2007/10/03)
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- Synthesis and Evaluation of 3-Substituted Analogues of 1,2,3,4-Tetrahydroisoquinoline as Inhibitors of Phenylethanolamine N-Methyltransferase
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1,2,3,4-Tetrahydroisoquinoline (THIQ) and aryl-substituted derivatives of THIQ are potent inhibitors of the enzyme that catalyzes the formation of epinephrine - phenylethanolamine N-methyltransferase (PNMT, E.C. 2.1.1.28).In previous studies, we found that substitution of the 3-position of THIQ with a methyl group resulted in enhanced activity as an inhibitor for 3-methyl-THIQ (8) with respect to THIQ itself.To more fully delineate this region of the PNMT active site, we have synthesized and evaluated other 3-substituted THIQ analogues that vary in both steric and electronic character.Extension of the methyl side chain in 8 by a single methylene unit results in diminished potency for 3-ethyl-THIQ (13), suggesting that this zone of the active site is spatially compact; furthermore, the region of steric intolerance may be located principally on only "one side" of the 3-position of bound THIQs, since the carbonyl containing (bent) analogues 3-(methoxycarbonyl)-THIQ (10) and 3-(aminocarbonyl)-THIQ (12) are much less capable of forming a strong enzyme-inhibitor dissociable complex compared to straight-chain derivatives possessing a similar steric component.The good activity of 3-(hydroxymethyl)-THIQ (11) as a PNMT inhibitor cannot be explained solely by steric tolerance for this side chain.We believe that an active-site amino acid residue capable of specific (i.e., hydrogen bond) interactions is located in close proximity to the 3-position of bound THIQs and that association of the OH functionality with this active-site residue results in the enhanced in vitro potency of this analogue (Ki = 2.4 μM) compared to that of THIQ (Ki = 10.3 μM).Incorporation of a hydroxymethyl substituent onto the 3-position of the potent PNMT inhibitor 7,8-dichloro-THIQ (SKF 64139, Ki = 0.24 μM) did not result in the same enhancement in inhibitor potency for 17 (Ki = 0.38 μM).This result suggests that simultaneous binding in an optional orientation of the aromatic halogens, secondary amine, and side-chain hydroxyl functionalities to the PNMT active site is not allowed in this analogue.
- Grunewald, Gary L.,Sall, Daniel J.,Monn, James A.
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p. 824 - 830
(2007/10/02)
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- 1,2,4-triazines
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Compounds of Formula I are novel and useful as cardiovascular agents, particularly anti-arrhythmic agents: STR1 or the 5-imino-tautomer thereof or a salt of either, wherein R1 is C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C3-10 cycloalkyl, any of which is optionally substituted, and R2 to R6 are independently selected from hydrogen, halogen atom, C1-6 alkyl, alkenyl or alkynyl (all optionally substituted by one or more of halogen, hydroxy and aryl, amino, mono- or di-substituted amino, alkoxy (optionally substituted by one or more of halogen, hydroxy and aryl), alkenyloxy, aryl, acyloxy, cyano, nitro, aryl and alkylthio groups or any adjacent two of R2 to R6 are linked to form a (--CH=CH--CH=CH--) group.
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