- Design, synthesis and biological evaluation of isoxazole-based CK1 inhibitors modified with chiral pyrrolidine scaffolds
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In this study, we report on the modification of a 3,4-diaryl-isoxazole-based CK1 inhibitor with chiral pyrrolidine scaffolds to develop potent and selective CK1 inhibitors. The pharmacophore of the lead structure was extended towards the ribose pocket of
- Luxenburger, Andreas,Schmidt, Dorian,Ianes, Chiara,Pichlo, Christian,Krüger, Marc,von Drathen, Thorsten,Brunstein, Elena,Gainsford, Graeme J.,Baumann, Ulrich,Knippschild, Uwe,Peifer, Christian
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- Synthesis, biological evaluation, and molecular modeling studies of chiral chloroquine analogues as antimalarial agents
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In a focused exploration, we designed, synthesized, and biologically evaluated chiral conjugated new chloroquine (CQ) analogues with substituted piperazines as antimalarial agents. In vitro as well as in vivo studies revealed that compound 7c showed potent activity (in vitro 50% inhibitory concentration, 56.98 nM for strain 3D7 and 97.76 nM for strain K1; selectivity index in vivo [up to at a dose of 12.5 mg/kg of body weight], 3,510) as a new lead antimalarial agent. Other compounds (compounds 6b, 6d, 7d, 7h, 8c, 8d, 9a, and 9c) also showed moderate activity against a CQ-sensitive strain (3D7) and superior activity against a CQ-resistant strain (K1) of Plasmodium falciparum. Furthermore, we carried out docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of all in-house data sets (168 molecules) of chiral CQ analogues to explain the structure-activity relationships (SAR). Our new findings specify the significance of the H-bond interaction with the side chain of heme for biological activity. In addition, the 3D-QSAR study against the 3D7 strain indicated the favorable and unfavorable sites of CQ analogues for incorporating steric, hydrophobic, and electropositive groups to improve the antimalarial activity.
- Kondaparla, Srinivasarao,Debnath, Utsab,Dola, Vasantha Rao,Sinha, Manish,Katti, Seturam B.,Soni, Awakash,Srivastava, Kumkum,Puri, Sunil K.
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- Synthesis and evaluation of chirally defined side chain variants of 7-chloro-4-aminoquinoline to overcome drug resistance in malaria chemotherapy
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A novel 4-aminoquinoline derivative [(S)-7-chloro-N-(4-methyl-1-(4-methyl-piperazin-1-yl)pentan-2-yl)-quinolin-4-amine triphosphate] exhibiting curative activity against chloroquine-resistant malaria parasites has been identified for preclinical development as a blood schizonticidal agent. The lead molecule selected after detailed structure-activity relationship (SAR) studies has good solid-state properties and promising activity against in vitro and in vivo experimental malaria models. The in vitro absorption, distribution, metabolism, and excretion (ADME) parameters indicate a favorable drug-like profile.
- Dola, Vasantha Rao,Soni, Awakash,Agarwal, Pooja,Ahmad, Hafsa,Raju, Kanumuri Siva Rama,Rashid, Mamunur,Wahajuddin, Muhammad,Srivastava, Kumkum,Haq,Dwivedi,Puri,Katti
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- Overcoming mutagenicity and ion channel activity: Optimization of selective spleen tyrosine kinase inhibitors
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Development of a series of highly kinome-selective spleen tyrosine kinase (Syk) inhibitors with favorable druglike properties is described. Early leads were discovered through X-ray crystallographic analysis, and a systematic survey of cores within a selected chemical space focused on ligand binding efficiency. Attenuation of hERG ion channel activity inherent within the initial chemotype was guided through modulation of physicochemical properties including log D, PSA, and pKa. PSA proved most effective for prospective compound design. Further profiling of an advanced compound revealed bacterial mutagenicity in the Ames test using TA97a Salmonella strain, and subsequent study demonstrated that this mutagenicity was pervasive throughout the series. Identification of intercalation as a likely mechanism for the mutagenicity-enabled modification of the core scaffold. Implementation of a DNA binding assay as a prescreen and models in DNA allowed resolution of the mutagenicity risk, affording molecules with favorable potency, selectivity, pharmacokinetic, and off-target profiles.
- Ellis, J. Michael,Altman, Michael D.,Bass, Alan,Butcher, John W.,Byford, Alan J.,Donofrio, Anthony,Galloway, Sheila,Haidle, Andrew M.,Jewell, James,Kelly, Nancy,Leccese, Erica K.,Lee, Sandra,Maddess, Matthew,Miller, J. Richard,Moy, Lily Y.,Osimboni, Ekundayo,Otte, Ryan D.,Reddy, M. Vijay,Spencer, Kerrie,Sun, Binyuan,Vincent, Stella H.,Ward, Gwendolyn J.,Woo, Grace H. C.,Yang, Chiming,Houshyar, Hani,Northrup, Alan B.
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p. 1929 - 1939
(2015/04/27)
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- New orally active dual enkephalinase inhibitors (DENKIs) for central and peripheral pain treatment
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Protecting enkephalins, endogenous opioid peptides released in response to nociceptive stimuli, is an innovative approach for acute and neuropathic pain alleviation. This is achieved by inhibition of their enzymatic degradation by two membrane-bound Zn-metallopeptidases, neprilysin (NEP, EC 3.4.24.11) and aminopeptidase N (APN, EC 3.4.11.2). Selective and efficient inhibitors of both enzymes, designated enkephalinases, have been designed that markedly increase extracellular concentrations and half-lives of enkephalins, inducing potent antinociceptive effects. Several chemical families of Dual ENKephalinase Inhibitors (DENKIs) have previously been developed but devoid of oral activity. We report here the design and synthesis of new pro-drugs, derived from co-drugs combining a NEP and an APN inhibitor through a disulfide bond with side chains improving oral bioavailability. Their pharmacological properties were assessed in various animal models of pain targeting central and/or peripheral opioid systems. Considering its efficacy in acute and neuropathic pain, one of these new DENKIs, 19-IIIa, was selected for clinical development.
- Poras, Hervé,Bonnard, Elisabeth,Dangé, Emilie,Fournié-Zaluski, Marie-Claude,Roques, Bernard P.
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supporting information
p. 5748 - 5763
(2014/08/05)
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- Design, synthesis and evaluation of novel indole derivatives as AKT inhibitors
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Herein, we describe the discovery and synthesis of a new series of 1,2,4,7-tetra-substituted indole derivatives as novel AKT inhibitors by optimization of a weak hit methyl 4-(2-aminoethoxy)-1H-indole-2-carboxylate (1). Both representative compounds 6a and 6o exhibited the most potent inhibitory activities against AKT1, with inhibition rates of 72.5% and 78.6%, respectively, at concentrations of 10 nM. In addition, compounds 6a and 6o also potently inhibited the phosphorylation of the downstream GSK3 protein and displayed slightly better anti-proliferative activities in a prostate cancer cell line.
- Yang, Dezhi,Wang, Peng,Liu, Jianzhen,Xing, Hualu,Liu, Yang,Xie, Wencheng,Zhao, Guisen
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p. 366 - 373
(2014/01/17)
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- A rapid entry to amino acid derived diverse 3,4-dihydropyrazines and dihydro[1,2,3]triazolo[1,5-a]pyrazines through 1,3-dipolar cycloaddition
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An efficient, general and practical synthesis of diverse 3,4-dihydropyrazines, 6,7-dihydro-[1,2,3]triazolopyrazines and 7,8-dihydro-[1,2,3]triazolodiazepines through intramolecular 1,3-dipolar cycloaddition from amino acid derived common intermediates with high yields is described. Moreover, one-pot access to optically active 3-aryl substituted 6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazines in the palladium-copper co-catalytic system has also been achieved in this work. The easy substrate availability and operational simplicity make the process suitable for further exploration. This journal is the Partner Organisations 2014.
- Bera, Saurav,Panda, Gautam
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p. 3976 - 3985
(2014/06/09)
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- INTERMEDIATES OF SITAGLIPTIN AND PREPARATION PROCESS THEREOF
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Disclosed are intermediates of Sitagliptin, a preparation process thereof, and a process for synthesizing Sitagliptin using these intermediates. Sitagliptin is synthesized by using chiral amino compounds as a raw material, without having to build a chiral center with a chiral asymmetric catalytic hydrogenation, and high-pressure hydrogenation is avoided.
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- INTERMEDIATES OF SITAGLIPTIN AND PREPARATION PROCESS THEREOF
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Disclosed are intermediates of Sitagliptin, a preparation process thereof, and a process for synthesizing Sitagliptin using these intermediates. Sitagliptin is synthesized by using chiral amino compounds as a raw material, without having to build a chiral center with a chiral asymmetric catalytic hydrogenation, and high-pressure hydrogenation is avoided.
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- Simple and rapid synthesis of Nα-urethane protected β-amino alcohols and peptide alcohols employing HATU
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The activation of the Nα--urcihanc protected (Fmoc-/Boc-/Z-/Bsmoc) α-amino acids employing l-[bis(dimethylamino)- methylene]-lH-l,2,3-triazolo-[4,5-6]pyridinium.0hexa-flurophosphate-3-oxide (HATU) followed by reduction of the in situ generated -OAt ester with NaBH 4 results in the corresponding ss-amino alcohols in good yields. This synthesis is the first demonstration of the application of the efficient coupling agent HATU for practical synthesis of ss-amino alcohols. The protocol is general for all common N-protecting groups including the highly base sensitive Bsmoc group. The protocol has also been successfully extended for the synthesis of peptide alcohols.
- Surcshbabu, Vommina V.,Sudarshan,Chennakrishnareddy
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experimental part
p. 574 - 579
(2009/12/06)
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- ETHER DERIVATIVE
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The present invention relates to an ether derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof wherein each symbol is as defined in the description, and an ether derivative represented by the formula (III), a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof wherein each symbol is as defined in the description; a pharmaceutical composition containing the ether derivative; and a package containing the pharmaceutical composition and a description of use thereof. A pharmaceutical composition of the present invention, which contains this compound of the present invention has a superior anti-inflammatory and analgesic activity and is useful as various pharmaceutical agents such as an anti-inflammatory agent, an analgesic, a therapeutic agent for inflammatory bowel disease, a therapeutic agent for pollakiuria and/or incontinentia, a therapeutic agent for asthma and the like.
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Page/Page column 36
(2008/06/13)
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- Short and efficient synthesis of a vinyl-substituted tricyclic erythromycin derivative
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(Chemical Equation Presented) Tricyclic erythromycin A derivatives are known potent antibacterial agents, but the potential of substituted tricyclic erythromycin A derivatives remains largely unexplored. To study this lead, the tricyclic ring system was synthesized by an efficient three-step synthesis starting from the allylic alcohol utilizing a novel azidoisocyanate. These tricyclic analogues can be used as scaffolds to probe secondary ribosomal binding sites.
- Keyes, Robert F.,Carter, Justin J.,Zhang, Xiaolin,Ma, Zhenkun
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p. 847 - 849
(2007/10/03)
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- Exploration of the P1 SAR of aldehyde cathepsin K inhibitors.
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The synthesis and biological activity of a series of aldehyde inhibitors of cathepsin K are reported. Exploration of the properties of the S(1) subsite with a series of alpha-amino aldehyde derivatives substituted at the P(1) position afforded compounds with cathepsin K IC(50)s between 52 microM and 15 nM.
- Catalano, John G,Deaton, David N,Furfine, Eric S,Hassell, Annie M,McFadyen, Robert B,Miller, Aaron B,Miller, Larry R,Shewchuk, Lisa M,Willard Jr., Derril H,Wright, Lois L
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p. 275 - 278
(2007/10/03)
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- Radical cyclization in heterocycle synthesis. Part 10: A concise synthesis of (-)-kainic acid via sulfanyl radical addition-cyclization-elimination reaction
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Sulfanyl radical addition-cyclization-elimination of diallylamines in the presence of thiophenol and AIBN gave the 2,3,4-trisubstituted pyrrolidine in high yield. This reaction was extended to a radical cyclization using a catalytic amount of thiophenol. A successful application was demonstrated by the asymmetric synthesis of (-)-kainic acid. (C) 2000 Elsevier Science Ltd.
- Miyata, Okiko,Ozawa, Yoshiki,Ninomiya, Ichiya,Naito, Takeaki
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p. 6199 - 6207
(2007/10/03)
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- A mild, efficient, inexpensive, and selective cleavage of primary tert-butyldimethylsilyl ethers by oxone in aqueous methanol
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(formula presented) The use of a 50% aqueous methonolic solution of Oxone is described for the selective cleavage of primary tert-butyldimethylsilyl and aryl ethers at room temperature. This method enables one to deprotect tert-butyldimethylsilyl ethers of primary alcohols in the presence of tertbutyldimethylsilyl ethers of secondary and tertiary alcohols and phenols. The silyl ethers of phenols were deprotected at longer reaction times.
- Sabitha, Gowravaram,Syamala, Mandali,Yadav
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p. 1701 - 1703
(2008/02/11)
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- Efficient conversion of (S)-methionine into (R)-garner aldehyde
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An efficient method has been developed for the conversion of L-methionine into N,O-protected D-serinal (Garner aldehyde) in good overall yield.
- Ravi Kumar, Jalluri S.,Datta, Apurba
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p. 6779 - 6780
(2007/10/03)
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- Copper(II) in Organic Synthesis. XI. Evaluation of the Ligand Architecture on the Efficiency of a Copper(II) Catalyst for Enantioselective Michael Reactions.
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Several bis-copper(II) complexes with chiral ligands derived from 2-substituted 2-(salicylideneamino)ethanols have been tested as catalysts of enantioselective Michael reactions.The degree of enantioselection is strongly affected by the architecture of the ligand.The best result (75percent e.e.) was obtained for a ligand having a substituent potentially suitable to induce the formation of a bis-tetradentate copper(II) complex with a square pyramidal coordination.
- Desimoni, Giovanni,Dusi, Guglielmo,Faita, Giuseppe,Quadrelli, Paolo,Righetti, PierPaolo
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p. 4131 - 4144
(2007/10/02)
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- Inhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 8. Incorporation of amide or amine functionalities into a series of disubstituted ureas and carbamates. Effects of ACAT inhibition in vitro and efficacy in vivo
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A series of disubstituted ureas containing amide or amine groups was prepared and evaluated for their ability to inhibit acyl-CoA:cholesterol O- acyl transferase in vitro and to lower plasma total cholesterol in a variety of cholesterol-fed rat models in vivo. The presence of polar or ionizable functionalities within this class of compounds may impart greater aqueous solubility to those compounds and thus allow improved transport to the enzyme location within the intestinal enterocyte. Compounds from this class exhibit good cholesterol lowering in a chronic cholesterol-fed rat model of hypercholesterolemia even when dosed in an aqueous vehicle. In general, the amine-containing compounds were more potent and efficacious than the amides in the acute rat model of hypercholesterolemia. Further structure-activity relationship studies showed that the preferred position of the amide/amine group was β to the urea moiety and not α, and that in this series, the presence of a secondary amine (or amide) proton is required for good in vitro potency. One of these compounds, 9n(-), lowered plasma total cholesterol (- 47%) and elevated high-density lipoprotein cholesterol (+256%) when dosed in an aqueous vehicle to rats with preestablished hypercholesterolemia.
- O'Brien,Sliskovic,Blankley,Roth,Wilson,Hamelehle,Krause,Stanfield
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p. 1810 - 1822
(2007/10/02)
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- Potent and systemically active aminopeptidase N inhibitors designed from active-site investigation
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Derivatives of amino acids bearing various zinc-coordinating moieties (SH, COOH, CONHOH, and PO3H2) were synthesized and tested for their ability to inhibit aminopeptidase N (APN). Among them, β-amino thiols were found to be the most
- Fournie-Zaluski,Coric,Turcaud,Bruetschy,Lucas,Noble,Roques
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p. 1259 - 1266
(2007/10/02)
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- A safe, simple, one-pot preparation of N-derivatized β-amino alcohols and oxazolidinones from amino acids
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N-tert-Butoxycarbonyl, N-benzoyl, N-benzyloxycarbonyl, and oxazilidinone derivatives of β-amino alcohols have been prepared from amino acids in 72 to 91% yields through lithium aluminum hydride reduction followed by in situ derivatization.
- Correa,Denis,Greene
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- A Convenient One-Pot Conversion of N-Protected Amino Acids and Peptides into Alcohols
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N-Protected amino acids and peptides are converted to alcohols by chemoselective reduction of their corresponding mixed anhydrides with sodium borohydride in tetrahydrofuran with dropwise addition of methanol.
- Kokotos, George
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p. 299 - 301
(2007/10/02)
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