- Equilibrium studies on reactive extraction of α-cyclohexylmandelic enantiomers using hydrophilic β-Cyclodextrin derivatives extractants
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β-Cyclodextrin (β-CD) is negligibly soluble in organic liquids and can be modified to achieve a higher solubility in water. In this paper, racemic α-cyclohexyl-mandelic acid (α-CHMA) was separated by chiral reactive extraction with aqueous β-cyclodextrin derivatives. Hydroxypropyl-β-cyclodextrin (HP-β-CD), hydroxyethyl-β- cyclodextrin (HE-β-CD), and methyl-β-cyclodextrin (Me-β-CD) were selected as chiral selectors for reactive extraction of α-CHMA enantiomers from organic phase to aqueous phase. Factors affecting the extraction efficiency were investigated, including the types of organic solvents and β-CD derivatives, the concentrations of the chiral selector and α-CHMA enantiomers, pH and temperature. The experimental results demonstrate that HP-β-CD, HE-β-CD, and Me-β-CD have stronger recognition abilities for S-α-CHMA than for R-α-CHMA. Among the three derivatives, HP-β-CD shows the strongest separation factor for α-CHMA enantiomers. A high enantioseparation efficiency with a maximum separation factor (α) of 2.02 is observed at pH 2.5 and 5 °C.
- Tang, Kewen,Miao, Jiabing,Liu, Yongbing,Zhou, Tao,Song, Litao
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Read Online
- Enantioseparation of α-cyclohexylmandelic acid by solvent sublation
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Herein we focused on using a novel separation technology, solvent sublation, for the enantioseparation of α-cyclohexylmandelic acid (CHMA). The experiment was carried out in a conventional bubble column using d-iso-butyl tartrate (d-IBTA) and sodium dodecyl sulfate (SDS) as a chiral selector and surfactant, respectively (Fig. 7). Several important parameters influencing the separation performance, such as the type of organic phase, the pH in the aqueous phase, and the concentrations of CHMA, d-IBTA, and SDS were investigated. Under the optimal operating conditions, the enantiomeric excess and separation factor were 54.85% and 4.5, respectively. The yields of d-enantiomer and l-enantiomer were 82.20% and 38.94%, respectively. Finally, the thermodynamic properties of the separation were investigated, which indicated an enthalpy-controlled process. This technique is an efficient chiral separation method, with many advantages, such as low amounts of organic solvent and chiral selector required and easier realization of the multi-stage operation.
- Chen, Xiaoqing,Yang, Weijie,Jiang, Xinyu,Jiao, Feipeng,Tian, Lingxing
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Read Online
- Isothiourea-Catalyzed Acylative Kinetic Resolution of Tertiary α-Hydroxy Esters
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A highly enantioselective isothiourea-catalyzed acylative kinetic resolution (KR) of acyclic tertiary alcohols has been developed. Selectivity factors of up to 200 were achieved for the KR of tertiary alcohols bearing an adjacent ester substituent, with both reaction conversion and enantioselectivity found to be sensitive to the steric and electronic environment at the stereogenic tertiary carbinol centre. For more sterically congested alcohols, the use of a recently-developed isoselenourea catalyst was optimal, with equivalent enantioselectivity but higher conversion achieved in comparison to the isothiourea HyperBTM. Diastereomeric acylation transition state models are proposed to rationalize the origins of enantiodiscrimination in this process. This KR procedure was also translated to a continuous-flow process using a polymer-supported variant of the catalyst.
- Greenhalgh, Mark D.,Laina-Martín, Víctor,Neyyappadath, Rifahath M.,Qu, Shen,Smith, Andrew D.,Smith, Samuel M.
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supporting information
p. 16572 - 16578
(2020/09/09)
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- Intermolecular Radical Addition to Ketoacids Enabled by Boron Activation
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The intermolecular radical addition to the carbonyl group is difficult due to the facile fragmentation of the resulting alkoxyl radical. To date, the intermolecular radical addition to ketones, a valuable approach to construct quaternary carbon centers, remains a formidable synthetic challenge. Here, we report the first visible-light-induced intermolecular alkyl boronic acid addition to α-ketoacids enabled by the Lewis acid activation. The in situ boron complex formation is confirmed by various spectroscopic measurements and mechanistic probing experiments, which facilitates various alkyl boronic acid addition to the carbonyl group and prevents the cleavage of the newly formed C-C bond. Diversely substituted lactates can be synthesized from readily available alkyl boronic acids and ketoacids at room temperature merely under visible light irradiation, without any additional reagent. This boron activation approach can be extended to alkyl dihydropyridines as radical precursors with external boron reagents for primary, secondary, and tertiary alkyl radical additions. The pharmaceutically useful anticholinergic precursors are easily scaled up in multigrams under metal-free conditions in flow reactors.
- Xie, Shasha,Li, Defang,Huang, Hanchu,Zhang, Fuyuan,Chen, Yiyun
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supporting information
p. 16237 - 16242
(2019/10/14)
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- Nitrilases
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The invention relates to nitrilases and to nucleic acids encoding the nitrilases. In addition, methods of designing new nitrilases and methods of use thereof are also provided. The nitrilases have increased activity and stability at increased pH and temperature.
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Paragraph 0495
(2015/09/22)
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- Nitrilases, nucleic acids encoding them and methods for making and using them
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The invention relates to nitrilases and to nucleic acids encoding the nitrilases. In addition methods of designing new nitrilases and method of use thereof are also provided. The nitrilases have increased activity and stability at increased pH and temperature.
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Page/Page column 53; 60
(2016/01/09)
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- Enantioseparation of mandelic acid and α-Cyclohexylmandelic acid using an alcohol/salt-based aqueous two-Phase system
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An alcohol/salt-based aqueous two-phase system (ATPS) was employed for enantioseparation of (R,S)-mandelic acid (MA) and (R,S)-a-cyclohexylmandelic acid (a-CHMA). Sulfonated β-cyclodextrin (Sf-β-CD) with different degrees of substitution (DS) was consider
- Li, Fen-Fang,Tan, Zhi-Jian,Guo, Zhi-Feng
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p. 1539 - 1545
(2015/02/19)
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- Conclusive identification of the oxybutynin-hydrolyzing enzyme in human liver
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The aim of this study was to conclusively determine the enzyme responsible for the hydrolysis of oxybutynin in human liver. Hydrolysis in human liver microsomes (HLMs) and human liver cytosol (HLC) followed Michaelis-Menten kinetics with similar Km values. In recombinant human carboxylesterase (CES)-expressing microsomes, CES1 was much more efficient than CES2 and yielded a Km value more comparable with that found in HLMs or HLC than did CES2. A correlation analysis using a set of individual HLMs, in which both CESs acted independently showed that the hydrolysis rate of oxybutynin, correlated significantly with a CES1 marker reaction, clopidogrel hydrolysis, but not with a CES2 marker reaction, irinotecan (CPT-11) hydrolysis. Chemical inhibition studies using bis-(p-nitrophenyl) phosphate, clopidogrel, nordihydroguaiaretic acid, procainamide, physostigmine, and loperamide revealed that the effects of these compounds in HLMs, HLC, and recombinant CES1-expressing microsomes were similar, whereas those in CES2-expressing microsomes were clearly different. These results strongly suggest that CES1, rather than CES2, is the principal enzyme responsible for the hydrolysis of oxybutynin in human liver. Copyright
- Sato, Yuichiro,Miyashita, Aiji,Iwatsubo, Takafumi,Usui, Takashi
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experimental part
p. 902 - 906
(2012/07/14)
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- SUBSTITUTED PHENYLCYCLOHEXYLGLYCOLATES
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Disclosed herein are substituted phenylcyclohexylglycolate-based muscarinic acetylcholine receptor modulators of Formula I, processes of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 53
(2009/10/06)
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- Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters as potent and long-acting muscarinic antagonists with potential for minimal systemic exposure after inhaled administration: Identification of (3R)-3-{[hydroxy(di-2-thienyl)acetyl]oxy}-1-(3-phenoxypropyl)-1-azoniabicyclo[2. 2.2]octane bromide (aclidinium bromide)
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The objective of this work was to discover a novel, long-acting muscarinicM3 antagonist for the inhaled treatment of chronic obstructive pulmonary disease (COPD), with a potentially improved risk-benefit profile compared with current antimuscarinic agents. A series of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters were synthesized and evaluated. On the basis of its overall profile, (3R)-3-{[hydroxy(di-2-thienyl) acetyl]oxy}-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (aclidiniumbromide) emerged as a candidate for once-daily maintenance treatment of COPD. This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects. Aclidinium bromide is currently in phase III development for maintenance treatment of patients with COPD.
- Prat, María,Fernández, Dolors,Buil, M. Antonia,Crespo, María I.,Casals, Gaspar,Ferrer, Manuel,Tort, Laia,Castro, Jordi,Monleón, Juan M.,Gavaldà, Amadeu,Miralpeix, Montserrat,Ramos, Israel,Doménech, Teresa,Vilella, Dolors,Antón, Francisca,Huerta, Josep M.,Espinosa, Sonia,López, Manuel,Sentellas, Sonia,González, Marisa,Albertí, Joan,Segarra, Victor,Cárdenas, Alvaro,Beleta, Jorge,Ryder, Hamish
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experimental part
p. 5076 - 5092
(2010/03/01)
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- OLIGOMER-ANTICHOLINERGIC AGENT CONJUGATES
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The invention provides anticholinergic agents that are chemically modified by covalent attachment of a water-soluble oligomer. A conjugate of the invention, when administered by any of a number of administration routes, exhibits characteristics that are different as compared to the characteristics of the anticholinergic agent not attached to the water-soluble oligomer.
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Page/Page column 38
(2008/12/07)
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- Enzymatic resolution of hindered cyanohydrins, key precursors of muscarinic receptor antagonists
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Enantiomerically pure 1-cycloalkyl-1-hydroxy-1-phenylcyanohydrins, key precursors in the synthesis of (S)-oxybutynin and other antimuscarinic agents, have been successfully prepared via lipase-catalyzed kinetic resolutions. Pseudomonas cepacia and Candida antarctica lipase B have shown excellent enantioselectivities in hydrolysis and acylation processes, depending on the substrate structure and the reaction conditions. Furthermore, molecular modeling of phosphonate transition state analogue for the C. antarctica lipase B enzymatic hydrolysis resolution step supports these facts, which were experimentally observed.
- Recuero, Veronica,Ferrero, Miguel,Gotor-Fernandez, Vicente,Brieva, Rosario,Gotor, Vicente
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p. 994 - 1002
(2008/02/03)
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- Synthesis and optimization of novel and selective muscarinic M3 receptor antagonists
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A series of constrained piperidine analogues were synthesized as novel muscarinic M3 receptor antagonists. Evaluation of these compounds in binding assays revealed that they not only have high affinity for the M3 receptor but also have high selectivity over the M2 receptor.
- Kumar, Naresh,Kaur, Kirandeep,Aeron, Shelly,Dharmarajan, Sankaranarayanan,Silamkoti, Arun D.V.,Mehta, Anita,Gupta, Suman,Chugh, Anita,Gupta, Jang B.,Salman, Mohammad,Palle, Venkata P.,Cliffe, Ian A.
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p. 5256 - 5260
(2008/02/11)
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- PROCESS FOR PRODUCTION OF OPTICALLY ACTIVE α-SUBSTITUTED MANDELIC ACID COMPOUND
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Disclosed is a process for production of an optically active α-substituted mandelic acid compound (a compound useful as an intermediate for synthesis of a pharmaceutical or the like) in an industrially advantageous manner. The process comprising the steps of reacting a compound (I) with a compound (II) in the presence of an optically active cyclic secondary amine to yield a compound (III) and producing a compound (VI) via a compound (V): wherein each symbol is as defined in the description.
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Page/Page column 34-35
(2008/06/13)
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- Enantioselective synthesis of α-tertiary hydroxyaldehydes by palladium-catalyzed asymmetric allylic alkylation of enolates
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Chiral α-tertiary hydroxyaldehydes are very versatile building blocks in synthetic chemistry. Herein, we report the first examples of a catalytic asymmetric protocol for the synthesis of such compounds from readily available α-halo or α-hydroxy ketones or enol silyl ethers with excellent yields and enantioselectivity. Its synthetic utility is demonstrated in the short, efficient formal synthesis of (S)-oxybutynin. In this process, the chiral ligand controls the regioselectivity as well as the enantioselectivity. Copyright
- Trost, Barry M.,Xu, Jiayi,Reichle, Markus
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p. 282 - 283
(2007/10/03)
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- Chiral linker. Part 4: Diastereoselective addition of RZnX to α-keto esters using m-hydrobenzoin derived chiral auxiliaries in solution and on solid support and their application in the stereoselective synthesis of frontalin
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Two recently reported, m-hydrobenzoin derived open chain chiral auxiliaries, which were developed for application in either solution or immobilized on a solid support, were tested in the diastereoselective addition of RZnX to their corresponding phenylglyoxylates and pyruvates, respectively, resulting in diastereoisomeric excesses of up to >98% de. The optimized procedure was applied in the stereoselective synthesis of frontalin, the aggregation pheromone of pine bark beetles of the Dendroctonus family, by the use of both the solution phase and the polymer supported chiral auxiliary.
- Schuster, Christian,Knollmueller, Max,Gaertner, Peter
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p. 2430 - 2441
(2007/10/03)
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- An efficient asymmetric synthesis of (S)-2-cyclohexyl-2-phenylglycolic acid, the acid segment of oxybutynin
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An innovative and facile synthesis of the title compound has been developed starting from (R)-cyclohexylidene glyceraldehyde. The key step in the synthesis is a chiral template-driven Grignard addition with absolute diastereocontrol. The other attractive features are the operational simplicity and the use of inexpensive compounds/reagents.
- Roy, Siddharth,Sharma, Anubha,Chattopadhyay, Nilmadhav,Chattopadhyay, Subrata
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p. 7067 - 7069
(2007/10/03)
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- A practical synthesis of (S)-2-cyclohexyl-2-phenylglycolic acid via organocatalytic asymmetric construction of a tetrasubstituted carbon center
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(Chemical Equation Presented) A concise and enantioselective synthesis of (S)-2-cyclohexyl-2-phenylglycolic acid as a key intermediate for (S)-oxybutynin is reported. The crucial asymmetric tetrasubstituted carbon center was constructed with excellent stereoselectivity through the proline-catalyzed direct asymmetric aldol reaction between cyclohexanone and ethyl phenylglyoxylate under mild conditions.
- Tokuda, Osamu,Kano, Taichi,Gao, Wei-Guo,Ikemoto, Tetsuya,Maruoka, Keiji
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p. 5103 - 5105
(2007/10/03)
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- High performance liquid chromatographic determination of oxeladin citrate and oxybutynin hydrochloride and their degradation products
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Two high performance liquid chromatographic (HPLC) methods are presented for the determination of oxeladin citrate (OL) and oxybutynin hydrochloride (OB) and their degradation products. The first method was based on HPLC separation of OL from its degradation product using a Nucleosil C18 column with a mobile phase consisting of acetonitrile -0.1% phosphoric acid (60:40 v/v). The second method was based on HPLC separation of OB from its degradation product using a VP-ODS C18 column with a mobile phase consisting of acetonitrile/0.01:M potassium dihydrogen phosphate/diethylamine (60:40:0.2). Quantitation was achieved with UV detection at 220:nm based on peak area. The two HPLC methods were applied for the determination of OL or OB, their degradation products, methylparaben and propylparaben in pharmaceutical preparations. The proposed methods were used to investigate the kinetics of acidic and alkaline degradation processes of OL and OB at different temperatures and the apparent pseudofirst-order rate constant, half-life and activation energy were calculated. The pH-rate profiles of degradation of OL and OB in Britton-Robinson buffer solutions within the pH range 2-12 were studied.
- El-Gindy, Alaa
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p. 689 - 699
(2007/10/03)
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- Catalytic asymmetric synthesis of (S)-oxybutynin and a versatile intermediate for antimuscarinic agents
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A practical synthesis of (S)-oxybutynin, a muscarinic receptor antagonist, using catalytic enantioselective cyanosilylation of cyclohexyl phenyl ketone (9a) as a key step is described. The key reaction proceeded with 94% ee using 1 mol% of Gd-1 catalyst,
- Masumoto, Shuji,Suzuki, Masato,Kanai, Motomu,Shibasaki, Masakatsu
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p. 10497 - 10504
(2007/10/03)
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- Process for the synthesis of enantiomerically pure cyclohexylphenyl glycolic acid
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The present invention provides a process for the synthesis of enantiomerically pure cyclohexylphenyl glycolic acid of formula (1). The present invention more particularly relates to a process using cyclohexylphenyl ketone for the synthesis of enantiomeric
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- Stereoselective synthesis of α-alkyl-α-hydroxylphenylacetic acid. Part (I): Asymmetric alkylation of (S)-mandelic acid
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An effective asymmetric synthesis of α-alkyl-α-hydroxyl phenyl acetic acid using benzaldehyde as steric hindrance agent has been accomplished by utilising the readily available and inexpensive chiral starting material, (S)-mandelic acid. The ee was determined by 1H NMR with Eu(hfc) 3 as shift reagent.
- Han, Xiang-Yu,Liu, He,Liu, Chun-He,Wu, Bo,Zhong, Bo-Hua,Liu, Ke-Liang
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p. 816 - 817
(2007/10/03)
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- 3,6-DISUBSTITUTED AZABICYCLO [3.1.0]HEXANE DERIVATIVES USEFUL AS MUSCARINIC RECEPTOR ANTAGONISTS
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This invention generally relates to the derivatives of 3,6 disubstituted azabicyclo[3.1.0]hexanes. The compounds of this invention are muscarinic receptor antagonists which are useful, inter-alia, for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems mediated through muscarinic receptors. The invention also relates to a process for the preparation of compounds of the present invention, pharmaceutical compositions containing the compounds of the present invention and the methods for treating the diseases mediated through muscarinic receptors.
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- An asymmetric dihydroxylation route to (S)-oxybutynin
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An asymmetric synthesis of (S)-oxybutynin 1 is described using the Sharpless asymmetric dihydroxylation of α-cyclohexylstyrene as the key step.
- Gupta, Priti,Fernandes, Rodney A.,Kumar, Pradeep
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p. 4231 - 4232
(2007/10/03)
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- Production method of 2-cyclohexyl- 2-hydroxy-2-phenylacetic acid intermediate therefor and production method thereof
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The present invention relates to production of 2-cyclohexyl-2-hydroxy-2-phenylacetic acid useful as an intermediate for pharmaceutical products, by an industrial means, economically, safely in a good yield. Novel 2-(2′-cyclohexen-1′-yl)-2-hydroxy-2-phenylacetic acid ester obtained by reacting cyclohexene and benzoylformic acid ester in the presence of a Lewis acid is hydrolyzed and reduced to give 2-cyclohexyl-2-hydroxy-2-phenylacetic acid.
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- A large-scale asymmetric synthesis of (S)-cyclohexylphenyl glycolic acid
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A practical asymmetric synthesis of (S)-cyclohexylphenyl glycolic acid has been demonstrated at pilot scale. The key step is the asymmetric aldol reaction using the Seebach approach of self-replication of stereochemistry. (S)-Mandelic acid was converted i
- Su, Xiping,Bhongle, Nandkumar N.,Pflum, Derek,Butler, Hal,Wald, Stephen A.,Bakale, Roger P.,Senanayake, Chris H.
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p. 3593 - 3600
(2007/10/03)
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- A practical synthesis of (S)-oxybutynin
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(S)-Oxybutynin, an important drug acting as muscarinic receptor antagonist, was practically synthesized using catalytic enantioselective cyanosilylation of cyclohexyl phenyl ketone (6a) as a key step. Cyanohydrin 7a with 94% ee was obtained with 1 mol% of
- Masumoto, Shuji,Suzuki, Masato,Kanai, Motomu,Shibasaki, Masakatsu
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p. 8647 - 8651
(2007/10/03)
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- Production method of 2-cyclohexyl-2-hydroxy-2-phenylacetic acid intermediate therefor and production method thereof
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The present invention relates to production of 2-cyclohexyl-2-hydroxy-2-phenylacetic acid useful as an intermediate for pharmaceutical products, by an industrial means, economically, safely in a good yield. Novel 2-(2'-cyclohexen-1'-yl)-2-hydroxy-2-phenylacetic acid ester obtained by reacting cyclohexene and benzoylformic acid ester in the presence of a Lewis acid is hydrolyzed and reduced to give 2-cyclohexyl-2-hydroxy-2-phenylacetic acid.
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- Nucleophilic benzoylation using lithiated methyl mandelate as a synthetic equivalent of the benzoyl carbanion. Oxidative decarboxylation of α-hydroxyacids
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The synthesis of alkyl aryl ketones using lithiated methyl mandelate as a synthetic equivalent of the benzoyl carbanion is reported (Umpolung). The methodology involves alkylation of methyl mandelate, hydrolysis of the ester group and oxidative decarboxylation of the resulting α-hydroxyacids. The last step is carried out in a catalytic aerobic way using a Co(III) complex in the presence of pivalaldehyde under very mild and advantageous conditions. The procedure is also applied to methyl mandelates substituted on the aromatic ring.
- Blay, Gonzalo,Fernández, Isabel,Formentin, Pilar,Monje, Belén,Pedro, José R,Ruiz, Rafael
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p. 1075 - 1081
(2007/10/03)
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- Rigid aminoalcohol backbone as a highly defined chiral template for the preparation of optically active tertiary α-hydroxyl acids
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Constrained aminoalcohol derived-ketoester or amides have provided a new entry for the production of enantiopure acid 1 for (S)-oxybutynin.
- Senanayake, Chris H.,Fang, Kevin,Grover, Paul,Bakale, Roger P.,Vandenbossche, Charles P.,Wald, Stephen A.
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p. 819 - 822
(2007/10/03)
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- Catalytic aerobic oxidative decarboxylation of α-hydroxy-acids. Methyl mandelate as a benzoyl anion equivalent
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The monomeric square-planar cobalt(III) complex of bis-N,N'- disubstituted oxamides catalyses the oxidative decarboxylation of α-hydroxy acids with molecular oxygen/pivalaldehyde with very good yields. This reaction offers an interesting alternative in the use of methyl mandelate as a convenient benzoyl anion equivalent.
- Blay, Gonzalo,Fernandez, Isabel,Formentin, Pilar,Pedro, Jose R.,Rosello, Antonio L.,Ruiz, Rafael,Journaux, Yves
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p. 3327 - 3330
(2007/10/03)
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- Synthesis, antimuscarinic activity and quantitative structure-activity relationship (QSAR) of tropinyl and piperidinyl esters
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A series of tropinyl and piperidinyl esters was synthesized and evaluated for inhibitory activities on the endothelial muscarinic receptors of rat (M3) and rabbit (M2) aorta. Some of the esters (cyclohexylphenylglycolates and cyclohexylphenylpropionates) were found to be better antimuscarinic compounds than standard M2 and M3 inhibitors such as AFDX116 and 4-diphenylacetoxy-N-methylpiperidine (DAMP), with pKEC50 values in the range of 8-9. A few esters were found to be more selective M3 than M2 inhibitors, but these tended to have low activities. The hydrophobic, electronic and steric characteristics of these esters were correlated with antimuscarinic activity by using appropriate parameters representing hydrophobicity (HPLC capacity factor, log k(w), size (molecular volume) and electronic character (Taft's polar substituent constant δ and 13C chemical shift difference Δδ). Finally, 92% of the M2-inhibitory activities of the esters could be accounted for by the size and electronic character σ* of the side chain. In contrast, the M3-inhibitory activities of these esters were mainly attributed to the electronic nature (σ*, Δδ) of the side chain, with good activity being associated with electron-withdrawing groups. Visualization of the comparative molecular field analysis (CoMFA) steric and electrostatic fields provided further confirmation of the structure-activity relationship (SAR) derived from traditional quantitative structure-activity relationship (QSAR) approaches.
- Xu, Rong,Sim, Meng-Kwoon,Go, Mei-Lin
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p. 231 - 241
(2007/10/03)
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- Hydrolytic profile for ester- or amide-linkage by carboxylesterases pI 5.3 and 4.5 from human liver
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Carboxylesterases (EC 3.1.1.1) from human liver were purified using Q- Sepharose, Sephadex G-150, isoelectrofocusing and Con A-Sepharose. The calculated molecular mass of the pI 5.3 enzyme was 120 kDa and 61 kDa from the results of Sephadex G-150 gel filtration and SDS-polyacrylamide gel electrophoresis (PAGE), respectively, suggesting that this enzyme is a dimer. On the other hand, carboxylesterase pI 4.5, with a molecular-mass of 64 kDa, was a monomer. The activities of both enzymes were inhibited by typical serine enzyme inhibitors. Amino acid sequence analysis of the purified enzymes pI 5.3 and 4.5 showed high homology with rabbit carboxylesterase form 1 and 2, respectively. The results also suggested that carboxylesterase pI 5.3 is identical to the deduced amino acid sequence from cDNA for HUI, and that carboxylesterase pI 4.5 is identical to the deduced amino acid sequence from the cDNA registered as human carboxylesterase (hCE-2) in GenBank. We first purified carboxylesterase pI 4.5 and investigated its hydrolytic activity upon various drugs. The two enzymes differed in substrate specificity. Prodrugs of angiotensin-converting enzyme inhibitors, such as delapril and imidapril, were converted to active metabolites by carboxylesterase pI 5.3, but not by carboxylesterase pI 4.5. The hydrolysis velocity of temocapril by carboxylesterase pI 5.3 was 12-fold faster than by carboxylesterase pI 4.5. In contrast, aspirin oxybutynin and procaine were hydrolyzed by only carboxylesterase pI 4.5. We also found that an amide- linkage in drugs, except for that in aniracetam was not a good substrate for the two enzymes. Consequently, carboxylesterases pI 5.3 and 4.5 maybe involved in the metabolism of various drugs containing an ester-linkage.
- Takai, Satomi,Matsuda, Ayuka,Usami, Yoshiko,Adachi, Tetsuo,Sugiyama, Tadashi,Katagiri, Yoshihiro,Tatematsu, Masae,Hirano, Kazuyuki
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p. 869 - 873
(2007/10/03)
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- Agents for the treatment of overactive detrusor. III. Synthesis and structure-activity relationships of N-(4-amino-2-butynyl)acetamide derivatives
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A series of N-(4-amino-2-butynyl)acetamides were synthesized and examined for their inhibitory activity on detrusor contraction and mydriatic activity as an index of anticholinergic side effect. Among those compounds synthesized, (+)-2-cyclohexyl-N-(4-dimethylamino-2-butynyl)-2-hydroxy-2-phenylaceta mide hydrochloride ((+)-13b·HCl), 2-cyclohexyl-2-hydroxy-N-(4-methylamino-2-butynyl)-2-phenylacetamide hydrochloride (13c·HCl), N-(4-dimethylamino-2-butynyl)-2,2-diphenyl-2-hydroxyacetamide hydrochloride (14·HCl), and 2,2-diphenyl-N-(4-ethylamino-2-butynyl)-2-hydroxyacetamide hydrochloride (14b·HCl) showed equipotent inhibitory activity on detrusor contraction to oxybutynin (1) and less mydriatic activity. Further evaluation of these compounds as an agent for the treatment of overactive detrusor has been examined.
- Take,Okumura,Tsubaki,Terai,Shiokawa
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p. 1415 - 1423
(2007/10/02)
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- Dedoublement et determination de la configuration absolue des enantiomeres de l'acide (thienyl-3)-2 cyclohexyl-2 hydroxy-2 acetique. Application a la synthese d'esters anticholinergiques du quinuclidinol-3
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Enantiomeric 2-(3-thienyl)-2-cyclohexyl-2-hydroxy acetic acids 1 were obtained by the resolution of (+/-)-1 using (+)- and (-)-ephedrine as the resolving agents, and by asymmetric synthesis; (+)-1 was assigned S absolute configuration (i) by comparing the circular dichroism spectra of a series of derivatives of 1 with those of the corresponding derivatives of S-(+)-2-phenyl-2-cyclohexyl-2-hydroxy acetic acid 1', and (ii) by application of the quasi-racemate method.On transesterification of the methyl esters of 1, R-(+)-2 and S-(-)-2, with R-(-)- or S-(+)-1-azabicyclo-3-octanol (or 3-quinuclidinol), the four diastereoisomers of 3-quinuclidinyl 2-(3-thienyl)-2-cyclohexyl-2-hydroxy-acetate were obtained, i.e., (+)-2R, 3'S-6, (-)-2S, 3'R-6, (+)-2R, 3'R-7, and (-)-2S, 3'S-7.These compounds exhibited anticholinergic activity.
- Tambute, Andre,Collet, Andre
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