- Simultaneous determination of serine enantiomers in plasma using Mosher's reagent and stable isotope dilution gas chromatography-mass spectrometry
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D-Serine is a co-agonist of the N-methyl-D-aspartate receptor in glutamate neurotransmission and has been proposed as a potential therapeutic agent for schizophrenia. However, D-serine also acts as a nephrotoxic substance in rats at high doses. To investigate the pharmacokinetics and toxicokinetics of D-serine, a method for the stereoselective determination of serine enantiomers in rat plasma was developed using GC-MS with selected ion monitoring (GC-MS-SIM). DL-[2H3]Serine was used as an internal standard to account for losses associated with the extraction, derivatization and chromatography. Serine enantiomers were purified by cation-exchange chromatography using BondElut SCX cartridge and derivatized with HCl in methanol to form methyl ester followed by subsequent N,O-diacylation with optically active (+)-α-methoxy-α-trifluoromethylphenylacetyl chloride to form epimeric amide. Quantitation was performed by SIM of the molecular-related ions of the epimers in the chemical ionization mode. The intra- and inter-day reproducibility of the assay was less than 5% for D-serine and 3% for L-serine. The method was successively applied to study the pharmacokinetics of D-serine in rats. Copyright
- Hasegawa, Hiroshi,Shinohara, Yoshihiko,Masuda, Nami,Hashimoto, Takao,Ichida, Kimiyoshi
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Read Online
- Total synthesis of (-)-kainic acid and (+)-: Allo -kainic acid through SmI2-mediated intramolecular coupling between allyl chloride and an α,β-unsaturated ester
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A 3,4-disubstituted pyrrolidine ring was effectively cyclized through SmI2-mediated reductive coupling between allyl chloride and an α,β-unsaturated ester, although little has been reported about SmI2-promoted C-C bond formation of an allyl chloride with an α,β-unsaturated ester. Selection of either the 3,4-cis- or 3,4-trans-selective cyclization can be accomplished simply by changing the additives from NiI2 to HMPA during reductive cyclization conducted in H2O-THF. Total synthesis of (-)-kainic acid and (+)-allo-kainic acid, which are pyrrolidine alkaloids used in neuroscience and neuropharmacology as useful molecular probes, was successfully achieved by using the stereo-complementary ring closure reactions promoted by SmI2 for the construction of the 2,3,4-trisubsituted pyrrolidine scaffold of kainoids.
- Suzuki, Junya,Miyano, Natsumi,Yashiro, Shunpei,Umezawa, Taiki,Matsuda, Fuyuhiko
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Read Online
- N-Pyrazinoyl substituted amino acids as potential antimycobacterial agents-the synthesis and biological evaluation of enantiomers
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Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (Mtb), each year causing millions of deaths. In this article, we present the synthesis and biological evaluations of new potential antimycobacterial compounds containing a fragment of the first-line antitubercular drug pyrazinamide (PZA), coupled with methyl or ethyl esters of selected amino acids. The antimicrobial activity was evaluated on a variety of (myco)bacterial strains, including Mtb H37Ra, M. smegmatis, M. aurum, Staphylococcus aureus, Pseudomonas aeruginosa, and fungal strains, including Candida albicans and Aspergillus flavus. Emphasis was placed on the comparison of enantiomer activities. None of the synthesized compounds showed any significant activity against fungal strains, and their antibacterial activities were also low, the best minimum inhibitory concentration (MIC) value was 31.25 μM. However, several compounds presented high activity against Mtb. Overall, higher activity was seen in derivatives containing l-amino acids. Similarly, the activity seems tied to the more lipophilic compounds. The most active derivative contained phenylglycine moiety (PC-d/l-Pgl-Me, MIC 1.95 μg/mL). All active compounds possessed low cytotoxicity and good selectivity towards Mtb. To the best of our knowledge, this is the first study comparing the activities of the d- and l-amino acid derivatives of pyrazinamide as potential antimycobacterial compounds.
- Bárta, Pavel,Dole?al, Martin,Horá?ek, Ond?ej,Jand'Ourek, Ond?ej,Janou?ek, Ji?í,Juhás, Martin,Kone?ná, Klára,Ku?era, Radim,Ku?erová, Lucie,Kubí?ek, Vladimír,Kune?, Ji?í,Paterová, Pavla,Zitko, Jan
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- Catalytic Mechanism Study on the 1,2- and 1,4-Transfer Hydrogenation of Ketimines and β-Enamino Esters Catalyzed by Axially Chiral Biscarboline-Based Alcohols
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Axial N-O alcohols, which have two large carboline moieties connected to the axis were synthesized and used in catalytic enantioselective 1,2- and 1,4-transfer hydrogenations of total 26 ketimines and β-enamino esters. Excellent levels of enantioselectivity ranging from 91% to 99% were achieved by using catalyst (aS)-(S)-3,3′-bis((S)-2-(hydroxymethyl)pyrrolidine-1-carbonyl)-9,9′-dimethyl-9H,9′H-[1,1′-bipyrido[3,4-b]indole] 2-oxide. Interestingly, a mixture of (aS)-(S)-3,3′-bis((S)-2-(hydroxymethyl)pyrrolidine-1-carbonyl)-9,9′-dimethyl-9H,9′H-[1,1′-bipyrido[3,4-b]indole] 2-oxide and (aR)-(S)-3,3′-bis((S)-2-(hydroxymethyl)pyrrolidine-1-carbonyl)-9,9′-dimethyl-9H,9′H-[1,1′-bipyrido[3,4-b]indole] 2-oxide was also able to provide high enantioselectivities up to 95% that is the same as that using pure (aS)-(S)-3,3′-bis((S)-2-(hydroxymethyl)pyrrolidine-1-carbonyl)-9,9′-dimethyl-9H,9′H-[1,1′-bipyrido[3,4-b]indole] 2-oxide. A plausible catalytic mechanism was suggested and total four kinds of transition states (TS) including almost 60 TS structures were investigated using density functional theory (DFT) with different basis sets such as 6-311G(2d,p). The predicted activation energy data are consistent with the experimental results. (Figure presented.).
- Dong, Mengxian,Wang, Jie,Wu, Shijie,Zhao, Yang,Ma, Yangyang,Xing, Yongfei,Cao, Fei,Li, Longfei,Li, Zhenqiu,Zhu, Huajie
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supporting information
p. 4602 - 4610
(2019/08/30)
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- HETEROCYCLIC COMPOUNDS FOR THE TREATMENT OF ABNORMAL CELLULAR PROLIFERATION
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This invention is in the area of heterocyclic-based compounds for the treatment of disorders involving abnormal cellular proliferation, including but not limited to tumors and cancers.
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Page/Page column 127-128
(2019/07/20)
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- A formal synthesis of (–)-kainic acid by means of SMI2-mediated radical cyclization
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A formal synthesis of (–)-kainic acid (1) starting from the known D-serine derivative 9 has been established in 14 steps. Construction of all the stereogenic centers on the pyrrolidine core of 1 was successfully achieved by application of SmI2-mediated radical cyclization to the α,β-unsaturated ester having an alkyne moiety, followed by hydroxy group directed diastereoselective hydrogenation over Wilkinson’s catalyst.
- Takahashi, Kazunori,Ito, Takumi,Yamada, Wataru,Tsubuki, Masayoshi,Honda, Toshio
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p. 882 - 894
(2018/06/04)
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- Synthesis, insecticidal activities and SAR studies of novel anthranilic diamides containing trifluoroethoxyl substituent and chiral amino acid moieties
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Ryanodine receptors (RyRs) activator has become one class of popular insecticide because of its unique mode of action. In order to find more new RyRs activators as insecticidal agents, a series of 18 novel chiral anthranilic diamides were designed by introducing the D-alanine acid and D-serine acid esters as well as trifluoroethoxyl group into the anthranilic diamide skeleton and synthesized successfully based on anthranilic diamide and FKI-1033 structures. The structures of the title compounds Ia–i and IIa–i were confirmed by melting points, 1H NMR, 13C NMR, elemental analysis and specific optical rotation analysis. The preliminary bioassay results indicated that most of the title compounds exhibited considerable larvicidal activities against oriental armyworm at 10 mg/L, especially Ib, Ie and IIh showed remarkable insecticidal activities at 0.5 mg/L. The larvicidal activity against diamondback moth of Ia and IId were 80% and 90% respectively at 0.0001 mg/L, which was similar to that of chlorantraniliprole. The relationship between structure and insecticidal activity was analyzed to reveal a possible co-regulated effect of the chiral amino acid ester, halogen atom or cyano group, and trifluoroethyloxyl group of the skeleton structures of the title compounds, which will provide useful information for guiding the design and discovery of new RyRs activators and insecticidal agrochemicals.
- Zhou, Shaa,Zhou, Sha,Xie, Yongtao,Meng, Xiangde,Wang, Baolei,Xiong, Lixia,Yang, Na,Li, Zhengming
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supporting information
p. 1254 - 1256
(2017/11/24)
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- 1-HETEROARYL-INDOLINE-4-CARBOXAMIDES AS MODULATORS OF GPR52 USEFUL FOR THE TREATMENT OR PREVENTION OF DISORDERS RELATED THERETO
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The present invention relates to compounds of Formula (la) and pharmaceutical compositions thereof that modulate the activity of GPR52. Compounds of the present invention and pharmaceutical compositions thereof are directed to methods useful in the treatment of a GPR52-mediated disorder (e.g., Huntington's disease, schizophrenia, bipolar disorder, attention deficit hyperactivity disorder (ADHD), or Tourette's syndrome); an extrapyramidal or movement disorder; a motor disorder; a hyperkinetic movement disorder; a psychotic disorder; catatonia; a mood disorder; a depressive disorder; an anxiety disorder; obsessive-compulsive disorder (OCD); an autism spectrum disorder; a prolactin-related disorder (e.g., hyperprolactinemia); a neurocognitive disorder; a trauma- or stressor-related disorder (e.g., posttraumatic stress disorder (PTSD)); a disruptive, impulse-control, or conduct disorder; a sleep-wake disorder; a substance-related disorder; an addictive disorder; a behavioral disorder; hypofrontality; an abnormality in the tuberoinfundibular, mesolimbic, mesocortical, or nigrostriatal pathway; decreased activity in the striatum; cortical dysfunction; neurocognitive dysfunction; and conditions related thereto.
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Page/Page column 90; 91
(2016/11/17)
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- Docking model of the nicotinic acetylcholine receptor and nitromethylene neonicotinoid derivatives with a longer chiral substituent and their biological activities
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In the present study, nitromethylene neonicotinoid derivatives possessing substituents that contain a sulfur atom, oxygen atom or aromatic ring at position 5 on the imidazolidine ring were synthesized to evaluate their affinity for the nicotinic acetylcholine receptor (nAChR) and their insecticidal activity against adult female houseflies. Comparing the receptor affinity of the alkylated derivative with the receptor affinity of compounds possessing either ether or thioether groups revealed that conversion of the carbon atom to a sulfur atom did not influence the receptor affinity, whereas conversion to an oxygen atom was disadvantageous for the receptor affinity. The receptor affinity of compounds possessing a benzyl or phenyl group was lower than that of the unsubstituted compound. Analysis of the three-dimensional quantitative structure-activity relationship using comparative molecular field analysis demonstrated that steric hindrance of the receptor should exist around the C3 of an n-butyl group attached at position 5 on the imidazolidine ring. A docking study of the nAChR-ligand model suggested that the ligand-binding region expands as the length of the substituent increases by brushing against the amino acids that form the binding region. The insecticidal activity of the compounds was positively correlated with the receptor affinity by considering log P and the number of heteroatoms, including sulfur and oxygen atoms, in the substituents, suggesting that the insecticidal activity is influenced by the receptor affinity, hydrophobicity, and metabolic stability of the compounds.
- Nagaoka, Hikaru,Nishiwaki, Hisashi,Kubo, Takuya,Akamatsu, Miki,Yamauchi, Satoshi,Shuto, Yoshihiro
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p. 759 - 769
(2015/02/19)
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- Two rearrangement pathways in the geminal acylation of 2-methoxyoxazolidines leading to substituted 1,4-oxazines
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Lewis acid-mediated geminal acylation of 2-methoxyoxazolidines with five- or six-membered acyloins followed by heterocyclization afforded 1,4-oxazines fused to cyclopentenone or cyclohexenone rings. Overall yields ranged from 30 to 73%. The position of the carbonyl group in the products depended on whether or not water was present during the ringexpanding acyl migration step. The route lacking water during the acyl migration step was best conducted in one pot. The addition of water effected cleavage of a silyloxy group in the intermediate during the initial Mukaiyama aldol reaction prior to the acyl migration.
- Moulins, Jonathan R.,Hughes, Jeremy A.,Doyle, Lauren E.,Cameron, T. Stanley,Burnell, D. Jean
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p. 1325 - 1332
(2015/03/04)
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- Efficient Synthesis of N-Sulfonyl β -Arylmethylalaninates from Serine via Ring Opening of N-Sulfonyl Aziridine-2-carboxylate
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We report the efficient synthesis of N-sulfonyl β-arylalanines methyl ester through regioselective ring opening of N-protected aziridines by variety of heteroaryl C-nucleophiles. We have optimized synthesis of N-protected aziridines with versatile protecting groups to afford 4a-c, 6a, and 6b with moderate to good yields using sulfuryl chloride, triethyl amine, and toluene at -50 °C. The present work reports on the studies related to electronic effect of nitrogen substituent on aziridination from the inexpensive starting material DL-serine. The present investigation also reports the efficient synthesis of N-sulfonyl β-arylmethylalaninates (7a-e and 8a-e) by regioselective nucleophilic ring opening of N-sulfonamido-protected aziridines using various aryl moieties such as C-nucleophiles and Lewis acids (InCl3, FeCl3, Cu(OTf)2) as catalysts and some trials by ring opening using Grignard reagent. GRAPHICAL ABSTRACT.
- Chaudhari, Prashant,Bari, Sanjay
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supporting information
p. 401 - 412
(2015/10/29)
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- Stereoselective synthesis of lanthionine derivatives in aqueous solution and their incorporation into the peptidoglycan of Escherichia coli
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The three diastereoisomers - (R,R), (S,S) and meso - of lanthionine were synthesized in aqueous solution with high diastereoselectivity (>99%). The (S) and (R) enantiomers of two differently protected sulfamidates were opened by nucleophilic attack of (R) or (S)-cysteine. Acidification and controlled heating liberated the free lanthionines. Using the same chemistry, an α-benzyl lanthionine was also prepared. The proposed method, which avoids the need of enrichment by recrystallization, opens the way to the labelling of these compounds with 35S. Furthermore, in vivo bioincorporation into Escherichia coli W7 was studied. No incorporation of α-benzyl lanthionine was observed. In contrast, meso-lanthionine can effectively replace meso-diaminopimelic acid in vivo, while in the presence of (R,R)-lanthionine the initial increase of bacterial growth was followed by cell lysis. In the future, meso-[35S]lanthionine could be used to study the biosynthesis of peptidoglycan and its turnover in relation to cell growth and division.
- Denoel, Thibaut,Zervosen, Astrid,Gerards, Thomas,Lemaire, Christian,Joris, Bernard,Blanot, Didier,Luxen, Andre
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p. 4621 - 4628
(2014/10/16)
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- NOVEL 6-BRIDGED HETEROARYLDIHYDROPYRIMIDINES FOR THE TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS INFECTION
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The invention provides novel compounds having the general formula: wherein R1, R2, R3 and R4 are as defined in the description and in the claims, as well as or pharmaceutically acceptable salts, or tautomerism isomers, or enantiomers, or diastereomers thereof. The invention also contains compositions including the compounds and methods of using the compounds.
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Paragraph 1000
(2014/12/09)
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- DIPEPTIDE AND TRIPEPTIDE EPOXY KETONE PROTEASE INHIBITORS
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Provided herein are dipeptide and tripeptide epoxy ketone protease inhibitors, methods of their preparation, related pharmaceutical compositions, and methods of using the same. For example, provided herein are compounds of Formula (X): and pharmaceutically acceptable salts and compositions including the same. The compounds and compositions provided herein may be used, for example, in the treatment of proliferative diseases including cancer and autoimmune diseases.
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Paragraph 00311; 00312
(2014/10/04)
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- AMIDINE SUBSTITUTED BETA - LACTAM COMPOUNDS, THEIR PREPARATION AND USE AS ANTIBACTERIAL AGENTS
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The present invention relates to novel β-lactam compounds of formula (I), their preparation and use. In particular, this invention relates to novel β-lactam compounds which are amidine substituted monobactam derivatives useful as antimicrobial agents and their preparation.
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Paragraph 00102; 00103
(2013/08/15)
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- PROCESSES FOR THE PREPARATION OF (R)-2-ACETAMIDO-N-BENZYL-3-METHOXYPROPIONAMIDE AND INTERMEDIATES THEREOF
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This invention relates to processes for the preparation of (R)-2- acetamido-/V-benzyl-3-methoxypropionamide (I) and intermediates thereof. Formula (I).
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Page/Page column 17
(2013/03/28)
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- BORON CONTAINING POLYBASIC BACTERIAL EFFLUX PUMP INHIBITORS AND THERAPEUTICS USES THEREOF
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Disclosed herein are polybasic bacterial efflux pump inhibitors containing boronic acid functionality and theft methods of synthesis, methods of use, and pharmaceutical compositions. Some embodiments include methods of treating or preventing a bacterial infection by co-administering to a subject infected with bacteria or at risk of infection with bacteria the efflux pump inhibitor with another anti-bacterial agent
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Page/Page column 59-60
(2012/08/28)
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- Transformation of d-serine to highly functionalized cyclohexenecarboxylates in study of oseltamivir synthesis
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In an attempted synthesis of oseltamivir, D-serine was used to prepare (R)-Garner aldehyde, which reacted with vinylzinc reagent to give an alcohol product predominating in the (1′R,4S)-isomer. After the alcohol was protected as p-methoxybenzyl ether, the N,O-acetal was hydrolyzed and oxidized to an aldehyde, which underwent Reformatsky-type reaction with ethyl α-(bromomethyl)acrylate by promotion of indium to give an addition product readily for ring-closure metathesis to afford 3-alkoxy-4-amido-5-hydroxy-1- cyclohexenecarboxylates. After activation of the 5-hydroxy group as methanesulfonate, an attempted substitution reaction with sodium azide gave unexpectedly a cyclic carbamate via an intramolecular nucleophilic attack of the 4-tert-butoxycarbamate group.
- Lai, Joshua,Fang, Jim-Min
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scheme or table
p. 426 - 435
(2012/08/07)
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- Catalytic asymmetric [4+2] annulation initiated by an aza-rauhut-currier reaction: Facile entry to highly functionalized tetrahydropyridines
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Under control: The first example of chiral amino phosphine catalysts for the title reaction between vinyl ketones and N-sulfonyl-1-aza-1,3-dienes has been developed. Under ambient conditions, this protocol provides straightforward access to densely functionalized, enantioenriched tetrahydropyridines with high levels of sterecontrol in good to excellent yields. Copyright
- Shi, Zugui,Yu, Peiyuan,Loh, Teck-Peng,Zhong, Guofu
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supporting information; scheme or table
p. 7825 - 7829
(2012/09/08)
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- Nature-inspired total synthesis of (-)-fusarisetin A
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A concise, protecting group-free total synthesis of (-)-fusarisetin A (1) was efficiently achieved in nine steps from commercially available (S)-(-)-citronellal. The synthetic approach was inspired by our proposed biosynthesis of 1. Key transformations of our strategy include a facile construction of the decalin moiety that is produced via a stereoselective IMDA reaction and a one-pot TEMPO-induced radical cyclization/aminolysis that forms the C ring of 1. Our route is amenable to analogue synthesis for biological evaluation.
- Xu, Jing,Caro-Diaz, Eduardo J. E.,Trzoss, Lynnie,Theodorakis, Emmanuel A.
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supporting information; experimental part
p. 5072 - 5075
(2012/05/07)
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- Comparison of liquid chromatography-isotope ratio mass spectrometry (LC/IRMS) and gas chromatography-combustion-isotope ratio mass spectrometry (GC/C/IRMS) for the determination of collagen amino acid δ13C values for palaeodietary and palaeoecological reconstruction
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Results are presented of a comparison of the amino acid (AA) δ13C values obtained by gas chromatography-combustion-isotope ratio mass spectrometry (GC/C/IRMS) and liquid chromatography-isotope ratio mass spectrometry (LC/IRMS). Although the primary focus was the compound-specific stable carbon isotope analysis of bone collagen AAs, because of its growing application for palaeodietary and palaeoecological reconstruction, the results are relevant to any field where AA δ13C values are required. We compare LC/IRMS with the most up-to-date GC/C/IRMS method using N-acetyl methyl ester (NACME) AA derivatives. This comparison involves the analysis of standard AAs and hydrolysates of archaeological human bone collagen, which have been previously investigated as N-trifluoroacetyl isopropyl esters (TFA/IP). It was observed that, although GC/C/IRMS analyses required less sample, LC/IRMS permitted the analysis of a wider range of AAs, particularly those not amenable to GC analysis (e.g. arginine). Accordingly, reconstructed bulk δ13C values based on LC/IRMS-derived δ13C values were closer to the EA/IRMS-derived δ13C values than those based on GC/C/IRMS values. The analytical errors for LC/IRMS AA δ13C values were lower than GC/C/IRMS determinations. Inconsistencies in the δ13C values of the TFA/IP derivatives compared with the NACME- and LC/IRMS-derived δ13C values suggest inherent problems with the use of TFA/IP derivatives, resulting from: (i) inefficient sample combustion, and/or (ii) differences in the intra-molecular distribution of δ13C values between AAs, which are manifested by incomplete combustion. Close similarities between the NACME AA δ13C values and the LC/IRMS-derived δ13C values suggest that the TFA/IP derivatives should be abandoned for the natural abundance determinations of AA δ13C values.
- Dunn, Philip J. H.,Honch, Noah V.,Evershed, Richard P.
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experimental part
p. 2995 - 3011
(2012/05/20)
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- Discovery of DA-1229: A potent, long acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes
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A series of β-amino amide containing substituted piperazine-2-one derivatives was synthesized and evaluated as inhibitors of dipeptidyl pepdidase-4 (DPP-4) for the treatment of type 2 diabetes. As results of intensive SAR study of the series, (R)-4-[(R)-3-amino-4-(2,4,5-trifluorophenyl)- butanoyl]-3-(t-butoxymethyl)-piperazin-2-one (DA-1229) displayed potent DPP-4 inhibition pattern in several animal models, was selected for clinical development.
- Kim, Heung Jae,Kwak, Woo Young,Min, Jong Pil,Lee, Jae Young,Yoon, Tae Hyun,Kim, Ha Dong,Shin, Chang Yell,Kim, Mi Kyung,Choi, Song Hyen,Kim, Hae Sun,Yang, Eun Kyoung,Cheong, Ye Hwang,Chae, Yu Na,Park, Kyung Jin,Jang, Ji Myun,Choi, Soo Jung,Son, Moon Ho,Kim, Soon Hoe,Yoo, Moohi,Lee, Bong Jin
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scheme or table
p. 3809 - 3812
(2011/07/31)
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- Following the lipase catalyzed enantioselective hydrolysis of amino acid esters with capillary electrophoresis using contactless conductivity detection
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The progress of the enzymatic hydrolysis of racemic mixtures of the enantiomers of the methyl esters of serine and threonine was monitored. This was possible in a reaction vessel of 1.5 mL by direct sampling of volumes in the nanoliter-range directly into an electrophoresis capillary. Contactless conductivity detection was used for quantification as the analytes are not accessible by UV-detection in capillary electrophoresis. Porcine pancreatic lipase and wheat germ lipase both showed a preference for the L-enantiomers of both amino acid esters. The selectivity of the porcine lipase between the two L-esters of the two amino acids was also studied and it was found that the production of L-threonine had priority over L-serine.
- Schuchert-Shi, Aiping,Hauser, Peter C.
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experimental part
p. 331 - 335
(2010/11/16)
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- Stable aziridinium salts as versatile intermediates: Isolation and regio- and stereoselective ring-opening and rearrangement
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Rock trapping and exploration: Aziridinium bromide salts were discovered serendipitously during bromination of N,N-dicarboxymethylated β-amino alcohols. Regiospecific ring-opening and rearrangement of the isolated, surprisingly stable aziridinium salts produces useful molecules including C-functionalized oxomorpholines and α,β-unsaturated amines. 2009 Wiley-VCH Verleg GmbH & Co. KGaA, Weinheim.
- Song, Hyun A.,Dadwal, Mamta,Lee, Yeseul,Mick, Emily,Chong, Hyun-Soon
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supporting information; experimental part
p. 1328 - 1330
(2009/06/30)
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- The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K
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Odanacatib is a potent, selective, and neutral cathepsin K inhibitor which was developed to address the metabolic liabilities of the Cat K inhibitor L-873724. Substituting P1 and modifying the P2 side chain led to a metabolically robust inhibitor with a long half-life in preclinical species. Odanacatib was more selective in whole cell assays than the published Cat K inhibitors balicatib and relacatib. Evaluation in dermal fibroblast culture showed minimal intracellular collagen accumulation relative to less selective Cat K inhibitors.
- Gauthier, Jacques Yves,Chauret, Nathalie,Cromlish, Wanda,Desmarais, Sylvie,Duong, Le T.,Falgueyret, Jean-Pierre,Kimmel, Donald B.,Lamontagne, Sonia,Leger, Serge,LeRiche, Tammy,Li, Chun Sing,Masse, Frederic,McKay, Daniel J.,Nicoll-Griffith, Deborah A.,Oballa, Renata M.,Palmer, James T.,Percival, M. David,Riendeau, Denis,Robichaud, Joel,Rodan, Gideon A.,Rodan, Sevgi B.,Seto, Carmai,Therien, Michel,Truong, Vouy-Linh,Venuti, Michael C.,Wesolowski, Gregg,Young, Robert N.,Zamboni, Robert,Black, W. Cameron
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p. 923 - 928
(2008/12/22)
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- Synthesis and pharmacological evaluation of novel γ-aminobutyric acid type B (GABAB) receptor agonists as gastroesophageal reflux inhibitors
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We have previously demonstrated that the prototypical GABAB receptor agonist baclofen inhibits transient lower esophageal sphincter relaxations (TLESRs), the most important mechanism for gastroesophageal reflux. Thus, GABAB agonists could be exploited for the treatment of gastroesophageal reflux disease. However, baclofen, which is used as an antispastic agent, and other previously known GABAB agonists can produce CNS side effects such as sedation, dizziness, nausea, and vomiting at higher doses. We now report the discovery of atypical GABAB agonists devoid of classical GABAB agonist related CNS side effects at therapeutic doses and the optimization of this type of compound for inhibition of TLESRs, which has resulted in a candidate drug (R)-7 (AZD3355) that is presently being evaluated in man.
- Alstermark, Christer,Amin, Kosrat,Dinn, Sean R.,Elebring, Thomas,Fjellstr?m, Ola,Fitzpatrick, Kevin,Geiss, William B.,Gottfries, Johan,Guzzo, Peter R.,Harding, James P.,Holmén, Anders,Kothare, Mohit,Lehmann, Anders,Mattsson, Jan P.,Nilsson, Karolina,Sundén, Gunnel,Swanson, Marianne,Von Unge, Sverker,Woo, Alex M.,Wyle, Michael J.,Zheng, Xiaozhang
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supporting information; scheme or table
p. 4315 - 4320
(2009/05/30)
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- Examining the chirality, conformation and selective kinase inhibition of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino) piperidin-1-yl)-3-oxopropanenitrile (CP-690,550)
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Here, we examine the significance that stereochemistry plays within the clinically relevant Janus kinase 3 (Jak3) inhibitor 1 (CP-690,550). A synthesis of all four enantiopure stereoisomers of the drug was carried out and an examination of each compound revealed that only the enantiopure 3R,4R isomer was capable of blocking Stat5 phosphorylation (Jak3 dependent). Each compound was profiled across a panel of over 350 kinases, which revealed a high level of selectivity for the Jak family kinases for these related compounds. Each stereoisomer retained a degree of binding to Jak3 and Jak2 and the 3R,4S and 3S,4R stereoisomers were further revealed to have binding affinity for selected members of the STE7 and STE20 subfamily of kinases. Finally, an appraisal of the minimum energy conformation of each stereoisomer and molecular docking at Jak3 was performed in an effort to better understand each compounds selectivity and potency profiles.
- Jiang, Jian-Kang,Ghoreschi, Kamran,Deflorian, Francesca,Chen, Zhi,Perreira, Melissa,Pesu, Marko,Smith, Jeremy,Nguyen, Dac-Trung,Liu, Eric H.,Leister, William,Costanzi, Stefano,O'Shea, John J.,Thomas, Craig J.
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supporting information; experimental part
p. 8012 - 8018
(2009/12/07)
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- Synthesis and anticonvulsant activities of N-benzyl (2R)-2-acetamido-3-oxysubstituted propionamide derivatives
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Lacosamide has been submitted for regulatory approval in the United States and Europe for the treatment of epilepsy. Previous synthetic methods did not permit the elaboration of the structure-activity relationship (SAR) for the 3-oxy site in lacosamide. We report an expedient five-step stereospecific synthesis for N-benzyl (2R)-2-acetamido-3-oxysubstituted propionamide analogs beginning with d-serine methyl ester. The procedure incorporated alkyl (e.g. methyl, primary, secondary, and tertiary) and aryl groups at this position. The SAR for the 3-oxy site showed maximal activity in animal seizure models for small 3-alkoxy substituents.
- Morieux, Pierre,Stables, James P.,Kohn, Harold
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experimental part
p. 8968 - 8975
(2009/04/06)
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- Design, synthesis, and bioactivity of novel inhibitors of E. coli aspartate transcarbamoylase
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A series of inhibitors of the aspartate transcarbamoylase, an enzyme involved in pyrimidine nucleotide biosynthesis, has been synthesized. These inhibitors are analogues of a highly potent inhibitor of this enzyme, N-phosphonacetyl-l-aspartate (PALA). Analogues have been synthesized with modifications at the α- and β-carboxylates as well as at the aspartate moiety. The ability of these compounds to inhibit the enzyme was evaluated. These studies, with functional group modified PALA derivatives, showed that amide groups can be a useful substitute of the carboxylate in order to reduce the charge on the molecule, and indicate that the relative position of the functional group in the β-position is more critical than the nature of the functional group. Some of the molecules synthesized here are potent inhibitors of the enzyme.
- Eldo, Joby,Heng, Sabrina,Kantrowitz, Evan R.
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p. 2086 - 2090
(2007/10/03)
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- Novel aliphatic compounds, process for their preparation and their usage
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The present invention provides an aliphatic compound represented by the following formula (I) or pharmacologically acceptable salts thereof: where n denotes an integer of 1 to 11, and 1 denotes an integer of 1 to 16, the aliphatic compound being an optical isomer of the (2R,3S,2′S) configuration when the 8-position thereof is a double bond, or an optical isomer of the (2S,3R,2′RS) configuration when the 8-position is a single bond; methods for producing the compound or pharmacologically acceptable salts thereof; and uses of the compound in the treatment of cardiovascular diseases (e.g. arteriosclerosis, cardiac diseases), cancer, rheumatism, diabetic retinopathy, and respiratory diseases.
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Page/Page column 10-11
(2010/02/05)
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- Quantitative enzymatic protection of D-amino acid methyl esters by exploiting 'relaxed' enantioselectivity of penicillin-G amidase in organic solvent
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A quantitative method for enzymatic protection of esters of various d-amino acids in organic solvent is reported. The lower enantioselectivity displayed by penicillin-G amidase (PGA) from E. coli in organic solvent has been exploited for developing a facile, fast and quantitative method for protection of esters of various d-amino acids via N-acylation. The feasibility of the deprotection of the acylated products was also demonstrated by employing PGA from two different sources in aqueous media. Experimental results are in agreement with previous calculations based on in silico models of the enzyme active site.
- Carboni, Chiara,Quaedflieg, Peter J. L. M.,Broxterman, Quirinus B.,Linda, Paolo,Gardossi, Lucia
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p. 9649 - 9652
(2007/10/03)
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- Synthesis of oxazolidinyl azacycles via ring-closing olefin metathesis: A practical entry to the synthesis of deoxy-azasugars and hydroxypyrrolizidines
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Starting with D- and L-serines, an expedient method for the preparation of oxazolidinyl piperidines, azepenes and azacyclooctenes was illustrated as a route to various deoxy-azasugars and hydroxypyrrolizidines. The ring-closing olefin metathesis of oxazolidinyl di-olefins was used as a key-step to construct the azacycles. Consecutive epoxidation, hydrolysis and transannulation of oxazolidinyl azacyclooctene led to hydroxypyrrolizidines.
- Subramanian, Thangaiah,Lin, Chang-Ching,Lin, Chun-Cheng
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p. 4079 - 4082
(2007/10/03)
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- Stereoselective synthesis of β-amino alcohols: Practical preparation of all four stereomers of N-PMB-protected sphingosine from L- and D-serine
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Serine was efficiently converted to the N-p-methoxybenzyl (PMB) protected α'-amino enone derivative 6, which was reduced with Zn(BH4)2 to the corresponding anti-β-amino alcohol in >96% de. On the other hand, N- PMB-N-Boc-protected α'-amino enone derivative 8 was reduced by NaBH4 to syn-product with a diastereoselectivity of ca. 90%.
- Chung, Sung-Kee,Lee, Jae-Mok
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p. 1441 - 1444
(2007/10/03)
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- Structural determinants of substrates and inhibitors: Probing glutamate transporters with 2,4-methanopyrrolidine-2,4-dicarboxylate
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Using an intramolecular [2+2] photocyclization, 2,4-methanopyrrolidine- 2,4-dicarboxylate was prepared as a conformationally locked analogue of glutamate. This compound, in combination with two other pyrrolidine dicarboxylates, has been used to define the structural elements that differentiate substrate and nonsubstrate inhibitors of a high-affinity, sodium-dependent glutamate transporter.
- Esslinger, C. Sean,Koch, Hans P.,Kavanaugh, Michael P.,Philips, Dean P.,Chamberlin, A. Richard,Thompson, Charles M.,Bridges, Richard J.
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p. 3101 - 3106
(2007/10/03)
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- A formal synthesis of (+)-α-allokainic acid via sulfanyl radical addition-cyclization reaction
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Sulfanyl radical addition-cyclization of the diallylamines in the presence of thiophenol and AIBN gave the 2,3,4-trisubstituted pyrrolidines which were effectively converted into the known key intermediate for the synthesis of (+)-α-allokainic acid via conversion of the phenylsulfanylmethyl group into the isopropenyl group at the 4-position.
- Miyata, Okiko,Ozawa, Yoshiki,Ninomiya, Ichiya,Aoe, Keiichi,Hiramatsu, Hajime,Naito, Takeaki
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p. 321 - 333
(2007/10/03)
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- Grignard reactions to chiral oxazolidine aldehydes
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Modest to high levels of asymmetric induction are observed with Grignard additions to Garner type aldehydes. The resultant secondary alcohols are important precursors of chiral building blocks for asymmetric synthesis and we have demonstrated that they can be readily converted into their respective γ-hydroxy-β-amino alcohols and β-hydroxyamino acids. Additionally, aryloxy ethers, important components of many natural products, can be obtained from these precursors.
- Williams, Lorenzo,Zhang, Zhongda,Shao, Feng,Carroll, Patrick J.,Joullie, Madeleine M.
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p. 11673 - 11694
(2007/10/03)
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- Cinnamic acid derivatives, photocrosslinkable cinnamic acid-polymer derivative and crosslinked cinnamic acid polymer derivatives
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The invention provides a cinnamic acid derivative having a novel spacer introduced into cinnamic acid which is photodimerizable, a cinnamic acid-polymer derivative photocurable with high sensitivity and efficiency obtainable by introducing the above cinnamic acid derivative into a host polymer such as a glycosaminoglycan, and a photocrosslinked cinnamic acid-polymer derivative obtainable by exposing the same cinnamic aicd-polymer derivative to ultraviolet light irradiation.
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- A practical stereoselective synthesis of (2S, 3S)-3-hydroxyleucine
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A practical and convenient procedure is described for the preparation of gram quantities of (2S, 3S)-3-hydroxyleucine. The key step involves the triflate-mediated cyclization of spirooxazolidine 4 to the spirobicyclic compound 5, which is easily converted to the title compound in high yield.
- Williams, Lorenzo,Zhang, Zhongda,Ding, Xiaobin,Joullie, Madeleine M.
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p. 7031 - 7034
(2007/10/02)
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- New Route to Pyroglutamates via α-Chloro Amide Radical Cyclisation
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The tributyltin hydride mediated radical cyclisation of N-(α-chloroacetamido)dehydroalanine derivatives prepared from serine proceeds regioselectively to give pyroglutamates in 47-74percent yield-the cyclisation of the intermediate carbamoylmethyl radical proceeds in a 'disfavoured' 5-endo-trig-manner.
- Goodall, Karen,Parsons, Andrew F.
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p. 3257 - 3260
(2007/10/02)
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- Potential application of Sulfolobus solfataricus as catalyst in organic synthesis
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Sulfolobus solfataricus, a thermoacidophilic archaeon, has been utilized as catalyst for several enzymatic transformations such as carbonyl-alcohol oxidoreductions, synthesis of glycosides, kinetic resolution of aminoacid esters, etc.All these reactions have been carried out at 75 deg C in accordance with the thermophilic nature of the enzymes present in the organisms.
- Trincone, Antonio,Nicolaus, Barbara,Lama, Licia,Gambacorta, Agata
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- Enantiospecific synthesis of R- and S-5,6-dihydroxy-2-(N,N-di-n-propylamino)tetralins from serine
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The first enantiospecific synthesis of 5,6-dihydroxy-2-(N,N-di-n-propylamino)tetralin [5,6-(HO)2DPAT] is reported. Starting from D- or L-serine either enantiomer is readily available in high optical purity.
- Baxter,Murray,Taylor
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p. 2331 - 2334
(2007/10/02)
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