- Efficient synthesis of 5-(hydroxymethyl)piperazin-2-ones using automatically prepared chiral bromocarboxylic acid and Garner's aldehyde as versatile building blocks
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An efficient method for the synthesis of substituted 5-(hydroxymethyl)piperazin-2-ones was established by using an automated synthesis process. Thirteen piperazinones were synthesized from chiral α-bromocarboxylic acids and Garner's aldehyde which were prepared by using our originally developed automated synthesizer, ChemKonzert. The automated method of synthesizing chiral α-bromocarboxylic acids was efficient and safe because the rate of the dropwise addition of the reagent can be controlled using the automated synthesizer. This method is expected to contribute to the synthesis of pharmaceuticals.
- Masui, Hisashi,Naito, Kohei,Minoshima, Mai,Kusayanagi, Akira,Yosugi, Sae,Shoji, Mitsuru,Takahashi, Takashi
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supporting information
(2021/05/04)
-
- Direct synthesis of α-thio aromatic acids from aromatic amino acids
-
Modified amino acids are useful synthetic components in both chemistry and biology. Here we describe a simple, scalable two-step procedure to generate α-thio aromatic acids from aromatic amino acids with yields of up to 96%. Diazotization and α-lactone me
- Samuels, Eric R.,Sevrioukova, Irina F.
-
supporting information
p. 1140 - 1142
(2018/02/23)
-
- Benzoxazinone-containing 3,5-dimethylisoxazole derivatives as BET bromodomain inhibitors for treatment of castration-resistant prostate cancer
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The bromodomain and extra-terminal proteins (BET) have emerged as promising therapeutic targets for the treatment of castration-resistant prostate cancer (CRPC). We report the design, synthesis and evaluation of a new series of benzoxazinone-containing 3,5-dimethylisoxazole derivatives as selective BET inhibitors. One of the new compounds, (R)-12 (Y02234), binds to BRD4(1) with a Kd value of 110 nM and blocks bromodomain and acetyl lysine interactions with an IC50 value of 100 nM. It also exhibits selectivity for BET over non-BET bromodomain proteins and demonstrates reasonable anti-proliferation and colony formation inhibition effect in prostate cancer cell lines such as 22Rv1 and C4-2B. The BRD4 inhibitor (R)-12 also significantly suppresses the expression of ERG, Myc and AR target gene PSA at the mRNA level in prostate cancer cells. Treatment with (R)-12 significantly suppresses the tumor growth of prostate cancer (TGI = 70%) in a 22Rv1-derived xenograft model. These data suggest that compound (R)-12 is a promising lead compound for the development of a new class of therapeutics for the treatment of CRPC.
- Xue, Xiaoqian,Zhang, Yan,Wang, Chao,Zhang, Maofeng,Xiang, Qiuping,Wang, Junjian,Wang, Anhui,Li, Chenchang,Zhang, Cheng,Zou, Lingjiao,Wang, Rui,Wu, Shuang,Lu, Yongzhi,Chen, Hongwu,Ding, Ke,Li, Guohui,Xu, Yong
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supporting information
p. 542 - 559
(2018/05/24)
-
- Di(1-naphthyl) methanol ester of carboxylic acids for absolute stereochemical determination
-
The absolute stereochemistry of chiral carboxylic acids is determined as a di(1-naphthyl)methanol ester derivative. Computational scoring of conformations favoring either P or M helicity of the naphthyl groups, capable of exciton-coupled circular dichroic coupling, leads to a predicted stereochemistry for the derivatized carboxylic acids.
- Zhang, Jun,Sheng, Wei,Gholami, Hadi,Nehira, Tatsuo,Borhan, Babak
-
supporting information
p. 141 - 146
(2017/11/13)
-
- Substituted α-mercaptoketones, new types of specific neprilysin inhibitors
-
New neprilysin inhibitors containing an α-mercaptoketone HSC(R1R2)CO group, as zinc ligand were designed. Two parameters were explored for potency optimization: the size of the inhibitor which could interact with the S1, S
- Poras, Hervé,Patouret, Rémi,Leiris, Simon,Ouimet, Tanja,Fournié-Zaluski, Marie-Claude,Roques, Bernard P.
-
p. 3883 - 3890
(2017/07/27)
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- MIXED INHIBITORS OF AMINOPEPTIDASE N AND NEPRILYSIN
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Mixed inhibitors of aminopeptidase N and neprilysin are disclosed. Pharmaceutical compositions containing at least one of these compounds, used alone or in combination with morphine and derivatives thereof, endocannabinoids and inhibitors of endocannabinoid metabolism, GABA derivatives such as gabapentin or pregabalin, duloxetine or methadone, can be used as an analgesic, anxiolytic, antidepressant or anti-inflammatory.
- -
-
Paragraph 0194-0198
(2015/11/18)
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- Enantioselective protonation of α-hetero carboxylic acid-derived ketene disilyl acetals under chiral ionic Bronsted acid catalysis
-
Highly enantioselective protonation of α-halo and alkoxy carboxylic acid-derived ketene disilyl acetals is achieved by using P-spiro chiral diaminodioxaphosphonium barfate as a Bronsted acid catalyst, where the enantiofacial discrimination by the catalyst mainly stems from the recognition of the electronic difference between two substituents on the ketene disilyl acetal.
- Uraguchi, Daisuke,Kizu, Tomohito,Ohira, Yuki,Ooi, Takashi
-
supporting information
p. 13489 - 13491
(2015/01/09)
-
- Synthesis of enantiomerically enriched-bromonitriles from amino acids
-
Two methods were investigated for the preparation of six chiral-bromonitriles with different optic purities. The nitrous deamination of amino acids gives-bromoacids, which react with chlorosulfonyl isocyanate followed by triethylamine to afford-bromonitriles with moderate enantiomeric excess. However, the dehydration of corresponding-bromoamids using thionyl chloride gives-bromonitriles with good enantiomeric excess up to 94%. The use of phosphoryl chloride instead of thionyl chloride results in more than 30% racemization as determined by high-performance liquid chromatograpic analysis.
- Tka, Najeh,Kraem, Jamil,Hassine, Bechir Ben
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p. 735 - 743
(2013/01/15)
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- Syntheses of hydrazino peptides and conjugates
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(α-Benzyloxycarbonyl-aminoacyl)benzotriazolides (Cbz = benzyloxycarbonyl) underwent a coupling reaction with α-hydrazino acids under microwave irradiation to form hybrid hydrazino dipeptides (42-71 %). Chiral acylations of β-N-Cbz-α-hydrazino acylbenzotriazolides were successfully carried out with N-, S-, O-, and C-nucleophiles in yields of 49-88 %. Benzyloxycarbonyl-protected hybrid hydrazino dipeptides and benzyloxycarbonyl-protected hydrazino aminoacyl conjugates with N-, S-, O-, and C-nucleophiles were prepared by using benzotriazole methodology. Copyright
- Panda, Siva S.,El-Nachef, Claudia,Bajaj, Kiran,Katritzky, Alan R.
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p. 4156 - 4162
(2013/07/19)
-
- Stereoselective synthesis of γ-lactams from imines and cyanosuccinic anhydrides
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A reaction between imines and anhydrides has been developed with chiral disubstituted anhydrides and chiral imines. The synthesis of highly substituted γ-lactams with three stereogenic centers, including one quaternary center, proceeds at room temperature in high yield and with high diastereoselectivity in most cases. Enantiomerically pure alkyl-substituted anhydrides proceed with no epimerization, thus providing access to enantiomerically pure penta-substituted lactam products.
- Tan, Darlene Q.,Younai, Ashkaan,Pattawong, Ommidala,Fettinger, James C.,Cheong, Paul Ha-Yeon,Shaw, Jared T.
-
supporting information
p. 5126 - 5129
(2013/10/22)
-
- Preparation and evaluation at the delta opioid receptor of a series of linear Leu-enkephalin analogues obtained by systematic replacement of the amides
-
Leu-enkephalin analogues, in which the amide bonds were sequentially and systematically replaced either by ester or N-methyl amide bonds, were prepared using classical organic chemistry as well as solid phase peptide synthesis (SPPS). The peptidomimetics were characterized using competition binding, ERK1/2 phosphorylation, receptor internalization, and contractility assays to evaluate their pharmacological profile over the delta opioid receptor (DOPr). The lipophilicity (LogD7.4) and plasma stability of the active analogues were also measured. Our results revealed that the last amide bond can be successfully replaced by either an ester or an N-methyl amide bond without significantly decreasing the biological activity of the corresponding analogues when compared to Leu-enkephalin. The peptidomimetics with an N-methyl amide function between residues Phe and Leu were found to be more lipophilic and more stable than Leu-enkephalin. Findings from the present study further revealed that the hydrogen-bond donor properties of the fourth amide of Leu-enkephalin are not important for its biological activity on DOPr. Our results show that the systematic replacement of amide bonds by isosteric functions represents an efficient way to design and synthesize novel peptide analogues with enhanced stability. Our findings further suggest that such a strategy can also be useful to study the biological roles of amide bonds.
- Rochon, Kristina,Proteau-Gagne, Arnaud,Bourassa, Philippe,Nadon, Jean-Francois,Coite, Jerome,Bournival, Veronique,Gobeil, Fernand,Guerin, Brigitte,Dory, Yves L.,Gendron, Louis
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p. 1204 - 1216
(2013/09/23)
-
- Conformational preference in bis(porphyrin) tweezer complexes: A versatile chirality sensor for α-chiral carboxylic acids
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Metallated porphyrin tweezers have demonstrated a remarkable ability to function as reporters of absolute stereochemistry for a number of different classes of organic molecules. Flexibility in binding, however, can result in an ensemble of different Exciton Coupled Circular Dichroism (ECCD) active conformations that could lead to variable results. Linker flexibility was found to be a key determinant of binding conformation. Experimental results indicate that a balance between linker flexibility and rigidity could yield an optimum porphyrin tweezer that stabilizes a common conformation for all bound chiral guests. This leads to a more simplified approach to absolute stereochemical determination of asymmetry for small organic molecules. This was demonstrated by the use of a C3-linked zincated porphyrin tweezer that yields a common conformational preference for a variety of α-chiral carboxylic acids derivatized with a diamine carrier. Copyright
- Tanasova, Marina,Borhan, Babak
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supporting information; experimental part
p. 3261 - 3269
(2012/07/01)
-
- A substrate-driven approach to determine reactivities of α,β-unsaturated carboxylic esters towards asymmetric bioreduction
-
The degree of C=C bond activation in the asymmetric bioreduction of α,β-unsaturated carboxylic esters by ene-reductases was studied, and general recommendations to render these "borderline-substrates" more reactive towards enzymatic reduction are proposed. The concept of "supported substrate activation" was developed. In general, an additional α-halogenated substituent proved to be beneficial for enzymatic activity, whereas β-alkyl or β-aryl substituents were detrimental for the reactivity of nonhalogenated substrates, and α-cyano groups showed little effect. The alcohol moiety of the ester functionality was found to have a strong influence on the reaction rate. Overall, activities were determined by both steric and electronic effects. Biotransformation: The asymmetric bioreduction of α,β-unsaturated carboxylic esters by ene-reductases could be tuned by varying the degree of C=C bond activation (see scheme). An additional α-halogenated substituent proved to be beneficial for enzymatic activity, whereas β-alkyl or β-aryl substituents were detrimental for the reactivity of nonhalogenated substrates. Copyright
- Tasnádi, Gábor,Winkler, Christoph K.,Clay, Dorina,Sultana, Nargis,Fabian, Walter M. F.,Hall, Mélanie,Ditrich, Klaus,Faber, Kurt
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supporting information; experimental part
p. 10362 - 10367
(2012/10/08)
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- α-amination of aldehydes catalyzed by in situ generated hypoiodite
-
The metal-free amination of different aldehydes is catalyzed by hypoiodite, which is generated by employing commercially available sodium percarbonate as the co-oxidant. This approach has several advantages: it is a metal-free oxidation that works under m
- Tian, Jie-Sheng,Ng, Kang Wai Jeffrey,Wong, Jiun-Ru,Loh, Teck-Peng
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supporting information
p. 9105 - 9109
(2012/10/29)
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- Triazolium Carbene Catalysts and Stereoselective Bond Forming Reactions Thereof
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Provided herein are triazolium carbine catalysts useful for asymmetric hydration, fluorination, and deuteration, and processes for their preparation. Also provided are synthetic reactions in which these catalysts are used, in particular, in stereoselective formation of carbon-chlorine, carbon-hydrogen, carbon-fluorine, and carbon-deuterium bonds.
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Page/Page column 8
(2011/10/04)
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- Biocatalyzed enantioselective reduction of activated C=C bonds: Synthesis of enantiomerically enriched α-halo-β-arylpropionic acids
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The enantioselective biocatalyzed reduction of the C=C bond of some (Z)-methyl α-halo-β-arylacrylates was investigated. The reaction was performed by baker's yeast fermentation and Old Yellow Enzymes 1-3 mediated biotransformations. The final products wer
- Brenna, Elisabetta,Gatti, Francesco G.,Manfredi, Alessia,Monti, Daniela,Parmeggiani, Fabio
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experimental part
p. 4015 - 4022
(2011/09/15)
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- Indium-mediated Reformatsky-Claisen rearrangement
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A new variant of the Reformatsky-Claisen rearrangement is described. The reaction of substituted allyl α-bromoacetates with indium and indium(III) chloride under ultrasonication provides a general entry into the functionalized synthon.
- Ishihara, Jun,Watanabe, Yuki,Koyama, Noriko,Nishino, Yukihiro,Takahashi, Keisuke,Hatakeyama, Susumi
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body text
p. 3659 - 3667
(2011/06/21)
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- An unusual conformation of α-haloamides due to cooperative binding with zincated porphyrins
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CD and NMR spectroscopic evidence of cooperative binding between an α-halogen atom and a carboxamide group with a zinc porphyrin leads to an unprecedented conformation for the determination of the absolute stereochemistry of α-haloamides (α-halocarboxylic acids derivatized with 1,4-phenylenediamine) through the use of exciton-coupled circular dichroism (ECCD). With the use of chiral lactams, whose rotomeric contributions are minimized, both ECCD and NMR spectroscopy demonstrate that the porphyrin favors binding to the side of the sterically more demanding halogen atom as compared to the smaller hydrogen atom. In all, the data is strongly suggestive of an unusual conformation not observed before for α-chiral amides. A mnemonic for determining the absolute stereochemistry of α-halogenated carboxylic acids is provided.
- Tanasova, Marina,Yang, Qifei,Olmsted, Courtney C.,Vasileiou, Chrysoula,Li, Xiaoyong,Anyika, Mercy,Borhan, Babak
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supporting information; experimental part
p. 4242 - 4253
(2011/02/25)
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- METHODS AND MATERIALS FOR PREPARING ORGANIC COMPOUNDS FROM PRIMARY AMINES
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Methods are disclosed for the conversion of primary amines to other functional groups. The methods can be used to prepare chiral organic compounds, including organic alcohols and organic halides. The methods can be carried out by treating a primary amine with an activating agent and a nitrosyl agent to produce the transformed compound along with nitrous oxide.
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Page/Page column 24-27
(2008/06/13)
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- New scalable asymmetric aminomethylation reaction for the synthesis of β2-amino acids
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β-Amino acids are useful tools in the design of peptidomimetics, and the development of new methods for their syntheses, particularly the synthesis of β2-amino acids, remains an important challenge. Here we report a new scalable route based on the aminomethylation of silyl ketene N,O-acetals by Mannich-type iminium electrophiles. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Moumne, Roba,Denise, Bernard,Guitot, Karine,Rudler, Henri,Lavielle, Solange,Karoyan, Philippe
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p. 1912 - 1920
(2008/02/06)
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- Efficient synthesis of β2-amino acid by homologation of α-amino acids involving the reformatsky reaction and Mannich-type imminium electrophile
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Development of new methods for the synthesis of β-amino acids is important as polymers of these compounds are promising peptidomimetic candidates in medicinal chemistry. We report here our findings on a new and highly efficient general strategy for the synthesis of β2-amino acids by homologation of α-amino acids, involving the Reformatsky reaction and Mannich-type imminium electrophile.
- Moumne, Roba,Lavielle, Solange,Karoyan, Philippe
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p. 3332 - 3334
(2007/10/03)
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- Fast and chemoselective N-debenzylation route to chiral 2-substituted thiomorpholin-3-ones
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Reaction time was found to be the critical parameter for the chemoselective N-debenzylation of thiomorpholin-3-one-derivatives with lithium in ammonia. This paper also reports the first preparation of a chiral 2-substituted thiomorpholine building block.
- Franceschini, Nicolas,Da Nascimento, Sophie,Miel, Hugues,Sonnet, Pascal
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p. 509 - 512
(2007/10/03)
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- Crystallization-induced chiral inversion as the key step for synthesis of (S)-2-acetylthio-3-phenylpropanoic acid from L-phenylalanine
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(Chemical Equation Presented) A novel crystallization-induced chiral inversion of (S)-2-bromo-3-phenylpropanoic acid to its (R)-enantiomer with excellent enantiomeric excess (96-99%) is achieved. Optically pure (S)-2-acetylthio-3-phenylpropanoic acid can
- Chen, Jason G.,Zhu, Jingyang,Skonezny, Paul M.,Rosso, Victor,Venit, John J.
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p. 3233 - 3235
(2007/10/03)
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- PROCESS FOR PREPARING (R)-2-BROMO-3-PHENYL-PROPIONIC ACID
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It is described a process for preparing (R)-2-bromo-3-phenyl-propionic acid starting from (D)-phenyl-alanine, sodium nitrite and concentrated hydrobromic acid in a mixture of an aqueous solvent and a solvent selected from the group consisting of halogenat
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- Ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate], processes for its preparation and its use
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The present invention relates to ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenyl-propanoate], the preparation of ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenyl-propanoate] from (2R)-2-bromo-3-phenylpropionic acid and ethylenediamine in 2-propanol, and the use of ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenyl-propanoate] for the preparation of ACE/NEP inhibitors.
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Page/Page column 5
(2008/06/13)
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- DERIVATIVES OF SUCCINIC AND GLUTARIC ACIDS AND ANALOGS THEREOF USEFUL AS INHIBITORS OF PHEX
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The present invention relates to derivatives of succinic and glutaric acids and analogues thereof, having the following general formula (I), useful as inhibitors of PHEX. These derivatives are useful for promoting generation of bone mass and treating or preventing diseases or conditions associated with a phosphate metabolism defect. Methods for preparation and intermediates are also disclosed.
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- PROCESS FOR PRODUCING OPTICALLY ACTIVE 2-SUBSTITUTED CARBOXYLIC ACID
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The present invention relates to a process for efficiently producing an optically active 2-bromocarboxylic acid and an optically active 2-sulfonyloxycarboxylic acid, which are important in the production of medicinal compounds and so forth. An optically active 2-sulfonyloxycarboxylic acid ester is subjected to deprotection under acid conditions to obtain an optically active 2-sulfonyloxycarboxylic acid. A metal bromide is caused to act on the acid to brominate it with configuration inversion at position 2 to thereby produce an optically active 2-bromocarboxylic acid. The resultant optically active 2-bromocarboxylic acid is isolated/purified by subjecting it to a step in which the acid is crystallized and separated as a salt with a base. Thus, an optically active 2-bromocarboxylic acid having a high chemical purity and high optical purity can be produced.
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- Process for the preparation of(R)-2-bromo-3-phenyl -propionic acid
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Process for the preparation of (R)-2-bromo-3-phenylpropionic acid starting from D-phenylalanine, sodium nitrite and HBr in an aqueous solution, the reaction being carried out in the presence of a bromide salt, at a temperature between ?10 and 30° C. The t
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- Method for the preparation of (s) -2-acetylthio-3-phenylpropionic acid
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Method for the preparation of (S)-2-acetylthio-3-phenylpropionic acid, wherein (R)-2-bromo-3-phenylpropionic acid is contacted with thioacetic acid and an organic base, for example triethylamine. Preferably the base is metered to a mixture of (R)-2-bromo-
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- Synthesis and Biological Activity of Hydroxamic Acid-Derived Vasopeptidase Inhibitor Analogues
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(Equation Presented) Syntheses of novel hydroxamic acid-derived azepinones containing pendant mercaptoacyl groups or formyl hydroxamates are described. These new analogues of therapeutically important ACE and NEP inhibitors include unprecedented changes a
- Walz, Andrew J.,Miller, Marvin J.
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p. 2047 - 2050
(2007/10/03)
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- Dynamic resolution of isomers and resolved isomers
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Provided is a dynamic resolution method of enriching a desired isomer of an alpha-substituted carboxylic acid relative to an undesired isomer, the method comprising: (a) in a solvent, contacting the alpha-substituted carboxylic acid, wherein the alpha sub
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- Synthesis and characterization of chiral N-O turns induced by α-aminoxy acids
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Chiral α-aminoxy acids of various side chains were synthesized with high optical purity starting from chiral α-amino acids. The conformations of diamides 13a-e, 15, and 16 were probed by using NMR, FT-IR, and CD spectroscopic methods as well as X-ray crystallography. The right-handed turns with eight-membered-ring intramolecular hydrogen bonds between adjacent residues (called the N-O turns) were found to be preferred for D-aminoxy acid residues, and they were independent of the side chains. The rigid chiral N-O turns should have great potential in molecular design.
- Yang,Li,Ng,Yan,Qu,Wu
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p. 7303 - 7312
(2007/10/03)
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- Design and synthesis of potent thiol-based inhibitors of endothelin converting enzyme-1
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Through directed screening of compounds prepared as metalloprotease inhibitors a compound, CGS 30084, that had potent endothelin converting enzyme-1 (ECE-1) in vitro inhibitory activity (IC50=77nM) was identified. Herein we report the synthesis and optimization of ECE-1 inhibitory activity of additional analogues from this lead. Compound 3c, the thioacetate methyl ester derivative of compound 4c, was found to be a long acting inhibitor of ECE-1 activity in rats after oral administration. (C) 2000 Elsevier Science Ltd.
- Fink, Cynthia A.,Moskal, Michael,Firooznia, Fariborz,Hoyer, Denton,Symonsbergen, David,Wei, Dongchu,Qiao, Ying,Savage, Paula,Beil, Michael E.,Trapani, Angelo J.,Jeng, Arco Y.
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p. 2037 - 2039
(2007/10/03)
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- Process for preparing (R)-2-bromo-3-phenyl-propionic acid
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It is described a process for preparing (R)-2-bromo-3-phenyl-propionic acid starting from (D)-phenyl-alanine, sodium nitrite and concentrated hydrobromic acid in a mixture of an aqueous solvent and a solvent selected from the group consisting of halogenat
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- Synthesis and activity of HIV protease inhibitors
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We report here the synthesis and activity of HIV protease inhibitors. In the first stage hydrophobic compounds incorporating a 'carba' bond surrogate or a beta-homologated residue were synthesized. Secondly, we synthesized cyclic compounds in which we incorporated 2-quinoline carboxylic acid in the P3 position and the amino-hydroxyindane moiety in the P'3. The last part of this work was dedicated to a structure/activity study of a peptide substrate. These modifications allowed us to work up the synthesis of new pseudopeptide bonds: amino-amide and hydroxy-amide. Compounds with activity in the micromolar range were actually a starting point for the synthesis of new protease inhibitors.
- Garrouste, Patrick,Pawlowski, Macek,Tonnaire, Thierry,Sicsic, Sames,Dumy, Pascal,De Rosny, Eve,Reboud-Ravaux, Michele,Fulcrand, Pierre,Martinez, Jean
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p. 423 - 436
(2007/10/03)
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- N-[MERCAPTOACYL(AMINO ACID OR PEPTIDE)] COMPOUNDS AND S-LIPOPHILIC ALIPHATIC CARBONYL DERIVATIVES THEREOF AS ANTIHYPERTENSIVES
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N-[Mercaptoacyl(amino acid or peptide)] compounds and S-lipophilic aliphatic carbonyl derivatives thereof, and pharmaceutical compositions comprising such compounds, as well as the use of these compounds as antihypertensives by the inhibition of neutral endopeptidase and/or peptidyldipeptidase A are disclosed. Methods for preparing the such compounds and derivatives are disclosed also.
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- Inhibition of carboxypeptidase A by (S)-2-mercapto-3-phenylpropanoic acid
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(S)-2-Mercapto-3-phenylpropanoic acid is an effective competitive inhibitor of carboxypeptidase A, comparable in potency to (S)-3-mercapto-2-benzylpropanoic acid.
- Lanthier, Christopher M.,MacKinnon, Gregory R.,Dmitrienko, Gary I.
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p. 2309 - 2310
(2007/10/03)
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- MERCAPTOACETYLAMIDE BICYCLIC LACTAM DERIVATIVES USEFUL AS INHIBITORS OF ENKEPHALINASE AND ACE
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The present invention relates to certain novel mercaptoacetylamide bicyclic lactam derivatives useful as inhibitors of enkephalinase and of ACE.These mercaptoacetylamide bicyclic lactam derivatives can be described by the following formula: STR1 whe
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-
-
- (R)- and (S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone as chiral auxiliaries for the asymmetric synthesis of α-hydroxy acids
-
Rac-α-bromo acids, rac-4, have been converted into(R)- or(S)-α-hydroxy acids, (R)- or (S)-9 by DCC-induced esterification with the chiral auxiliaries (R)or (S)-1, followed by reaction with sodium p-methoxyphenoxide in the presence of tetra-n-hexylammonium iodide, conditions of dynamic kinetic resolution, to give quite diastereoselectively the (αR,3S)- or (αS,3R)-α-(p-methoxyphenoxy) esters, 7, which were then oxidized with eerie ammonium nitrate and hydrolyzed under controlled acid conditions.
- Camps, Pelayo,Perez, Francesc,Soldevilla, Nuria
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p. 1877 - 1894
(2007/10/03)
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- Optimal recognition of neutral endopeptidase and angiotensin-converting enzyme active sites by mercaptoacyldipeptides as a means to design potent dual inhibitors
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An interesting approach for the treatment of congestive heart failure and chronic hypertension could be to avoid the formation of angiotensin II by inhibiting angiotensin converting enzyme (ACE) and to protect atrial natriuretic factor by blocking neutral endopeptidase 24.11 (NEP). This is supported by recent results obtained with potent dual inhibitors of the two zinc metallopeptidases, such as RB 105, HSCH2CH(CH3)PhCONHCH(CH3)COOH (Fournie-Zaluski et al. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 4072-4076), which reduces blood pressure in experimental models of hypertension, independently of the salt and renin angiotensin system status. In order to develop new dual inhibitors with improved affinities, long duration of action, and/or better bioavailabilities, various series of mercaptoacyldipeptides corresponding to the general formula HSCH(R1)CONHCH(R1')CON(R)CH(R2')COOH have been synthesized. The introduction of well-selected β-branched chains in positions R1 and R1', associated with a tyrosine or a cyclic amino acid in the C-terminal position, led to potent dual inhibitors of NEP and ACE such as 21 [N-[(2S)-2-mercapto- 3-methylbutanoyl]-Ile-Tyr] and 22 [N-[(2S)-2-mercapte-3-phenylpropanoyl]Ala- Pro] which have IC50 values in the nanomolar range for NEP and subnanomolar range for ACE. These compounds could have different modes of binding to the two peptidases. In NEP, the dual inhibitors seem to interact only with the S1' and S2' subsites, whereas additional interactions with the S1 binding subsite of ACE probably account for their subnanomolar inhibitory potencies for this enzyme. The localization of the Pro residue of 22 outside the NEP active site is supported by biochemical data using (Arg102,Glu)NEP and molecular modeling studies with thermolysin used as model of NEP. One hour after oral administration in mice of a single dose (2.7 x 10-5 mol/kg), 21 inhibited 80% and 36% of kidney NEP and lung ACE, respectively, while 22 inhibited 40% of kidney NEP and 56% of lung ACE.
- Coric, Pascale,Turcaud, Serge,Meudal, Hervé,Roques, Bernard Pierre,Fournie-Zaluski, Marie-Claude
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p. 1210 - 1219
(2007/10/03)
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- SUBSTITUTED AZEPINONE DUAL INHIBITORS OF ANGIOTENSIN CONVERTING ENZYME AND NEUTRAL EXDOPEPTIDASE
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Compounds of the formula STR1 are disclosed as possessing inhibitory activity against angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) and thus being useful as cardiovascular agents. Processes for preparing these compounds are also disclosed.
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- Synthesis of C2-symmetric HIV-protease inhibitors with sulfur-containing central units
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Sulfide-, sulfoxide-, and sulfone- containing C2-symmetric peptide analogs were obtained stereospecifically starting from phenylalanine. The compounds were evaluated as potential HIV-protease inhibitors and found to be inactive within the limit
- Spaltenstein,Leban,Furfine
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p. 1457 - 1460
(2007/10/02)
-
- Acylmercaptoalkanoyldipeptides, methods of preparation and their therapeutic use
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This invention is directed to a compound of the formula that inhibits simultaneously neutral endopeptidase and peptidyldipeptidase A and is useful in treating hypertension. The invention is also directed to the preparation of the compound, pharmaceutical compositions containing it, and methods for its pharmaceutical use.
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- Mercaptoacetylamide tricyclic derivatives useful as inhibitors of enkephalinase
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The present invention relates to novel mercaptoacetylamide tricyclic derivatives useful as inhibitors of enkephalinase.
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- Cyclic RGD Peptide Analogues as Antiplatelet Antithrombotics
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Stimulation of platelets activates GPIIbIIIa, the heterodimeric integrin receptor, to bind fibrinogen (Fg), which results in platelet aggregation.GPIIbIIIa/Fg binding inhibitors are potentially suitable for acute use during and after thrombolytic therapy
- Barker, Peter L.,Bullens, Sherron,Bunting, Stuart,Burdick, Daniel J.,Chan, Kathryn S.,et al.
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p. 2040 - 2048
(2007/10/02)
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- Nucleophilic Substitution Reactions of Alkyl Halides By Using New Polymer-Supported Reagents Containing Hemin
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A new polymer reagent consisting of hemin, divinylbenzene, and 2-methyl-5-vinylpyridine was synthesized by suspension copolymerization.Substitution reactions of primary, secondary, and tertiary alkyl halides with the hemin copolymer combined with cyanide, azide, and thiocyanate ions were given satisfactory yields.This reaction mechanism was revealed to be a SNi type on the basis of stereochemical study.The hemin copolymer was not only a polymer-supported reagent with functional capabilities, but also served to separate the product from the reaction mixture.
- Saito, Kiyoshi,Harada, Kaoru
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p. 2562 - 2566
(2007/10/02)
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