- Selective Allosteric Antagonists for the G Protein-Coupled Receptor GPRC6A Based on the 2-Phenylindole Privileged Structure Scaffold
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G protein-coupled receptors (GPCRs) represent a biological target class of fundamental importance in drug therapy. The GPRC6A receptor is a newly deorphanized class C GPCR that we recently reported for the first allosteric antagonists based on the 2-arylindole privileged structure scaffold (e.g., 1-3). Herein, we present the first structure-activity relationship study for the 2-arylindole antagonist 3, comprising the design, synthesis, and pharmacological evaluation of a focused library of 3-substituted 2-arylindoles. In a FRET-based inositol monophosphate (IP1) assay we identified compounds 7, 13e, and 34b as antagonists at the GPRC6A receptor in the low micromolar range and show that 7 and 34b display >9-fold selectivity for the GPRC6A receptor over related GPCRs, making 7 and 34b the most potent and selective antagonists for the GPRC6A receptor reported to date.
- Johansson, Henrik,Boesgaard, Michael Worch,N?rskov-Lauritsen, Lenea,Larsen, Inna,Kuhne, Sebastiaan,Gloriam, David E.,Br?uner-Osborne, Hans,Sejer Pedersen, Daniel
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Read Online
- Generation of Oxyphosphonium Ions by Photoredox/Cobaloxime Catalysis for Scalable Amide and Peptide Synthesis in Batch and Continuous-Flow
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Phosphine-mediated deoxygenative nucleophilic substitutions, such as the Mitsunobu reaction, are of great importance in organic synthesis. However, the conventional protocols require stoichiometric oxidants to trigger the formation of the oxyphosphonium i
- Chen, Xiangyang,Houk, Kendall N.,Mo, Jia-Nan,Su, Junqi,Umanzor, Alexander,Zhang, Zheng,Zhao, Jiannan
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supporting information
(2022/01/06)
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- New glycine derived peptides bearing benzenesulphonamide as an antiplasmodial agent
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In the tropics, malaria is among the most serious infectious diseases in developing countries. The discovery of the artemesinin antimalarial drug not too long ago was a major breakthrough in the effort to combat the malaria disease. However, recent reports of resistance even to combination therapy involving artemisinin are very worrisome and have led to the search for new chemical agents to sustain the fight against malaria. The carboxamide functionality has been shown to be an important pharmacophore in over 25% of commercial chemotherapeutic agents. Three benzensulphonamides (3a-c) were prepared from the reaction of the appropriate benzensulphonyl chloride (1a-c) and alanine (2) in aqueous basic medium. Eight tert-butylamino-oxo-ethylcarbamates (5a-h) were also prepared from reacting commercially available boc-glycine (4) and different amines using peptide coupling reagents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and 1-hydroxybenzotriazole (HOBt), with triethyl amine and dichloromethane (DCM) as solvents. The target compounds were prepared by reacting compounds 3a-c with compounds 5a-h in the presence of coupling reagents to get twenty four (24) different compounds. The compounds were characterized and evaluated for their antiplasmodial activity. Computed molecular descriptors and assessed biochemical parameters showed that the compounds were drug-like and safe. All the compounds had favourable binding interactions with residues at the PABA binding site of homologically modeled P. falciparum dihydropteroate synthase and henceforward the in vitro and in vivo antiplasmodial activities were evaluated. Compounds 7a-7x showed activity against P. falciparum (W2 strain) at MIC values ranging from 3.52 to 0.09 μM. Moreover, seven of the compounds (7c, 7d, 7i, 7j, 7p, 7r and 7s) showed better activity than quinine (MIC = 0.72 μM). In addition, 16 of the 24 compounds were found to clear more than 50 percent of P. berghei (NK-65 strain) from the blood of infected mice at 12 days post-infection. The percentages of parasites cleared by 20 mg kg-1 of the three most effective compounds (7g, 7n and 7r) were 74.98, 74.98 and 74.07, respectively. In conclusion, 7r (MIC 0.71 μM) from this class of glycine derived sulfonamides has the ability to clear 74.07% of P. berghei from blood of infected mice at 20 mg kg-1 and an interesting pharmacokinetic profile (MW = 430.31 Da, HBA = 7, HBD = 3, log?P = 2.56, NRB = 9 and TPSA = 104.37 ?2), which is in agreement with the Lipinski rule of 5 for a compound to be qualified as a drug candidate. 7r could serve as a lead in developing new antiplasmodial agents. This journal is
- Ugwuja, Daniel Izuchukwu,Okoro, Uchechukwu,Soman, Shubhanji,Ibezim, Akachukwu,Ugwu, David,Soni, Rina,Obi, Bonaventure,Ezugwu, James,Ekoh, Ogechi
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p. 3660 - 3674
(2021/03/03)
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- Synthesis, molecular docking and antimalarial activity of phenylalanine-glycine dipeptide bearing sulphonamide moiety
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Ten novel phenylalanine-glycine dipeptide sulphonamide conjugate were synthesized and characterized using 1HNMR, 13CNMR, FTIR and HRMS spectroscopic techniques. The in silico studies predicted better interactions of compounds with target protein residues and a higher dock score in comparison with standard drugs. The in vivo antimalarial study, hematological study, liver and kidney function test were evaluated on the synthesized compounds. Compounds 7h, 7i and 7j inhibited the parasite by 34.5–60.2% on day 4 of after-treatment exposure. Compound 7j inhibited the multiplication of the parasite by 60.2% on day 4 of after-treatment which was comparable with that of the standard drug with 68.8% inhibition at same day of after-treatment exposure.
- Ali, Rafat.,Aronimo, Babatunde. S.,Ezugwu, James. A.,Ibeji, Collins. U.,Okoro, Uchechukwu. C.,Ugwu, David. I.
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- Synthesis of protected α-amino acids: Via decarboxylation amination from malonate derivatives
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A general and efficient strategy for the synthesis of protected α-amino acids is reported. The method uses malonate derivatives as the starting materials and Cs2CO3 as a base at 60 degrees, giving α-amino acid derivatives in moderate yields by releasing CO2. This methodology shows broad substrate scope (primary and secondary acids), excellent functional group tolerance and high efficiency to give the desired products under mild reaction conditions. It also allows the construction of β and γ-amino acids and other unnatural products.
- Dai, Qipu,Fu, Hui,Hu, Changwen,Li, Peihe,Li, Xiaoying,Wang, Zheng
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p. 4439 - 4446
(2020/10/20)
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- Base catalytic decarboxylation amination preparation method of amino-acid ester/amide
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The invention discloses a base catalytic preparation method of alpha amino-acid ester/amide from beta carbonyl acid, and belongs to the field of organic chemistry. According to the method, malonate is taken as a raw material, single hydrolysis is carried out to obtain beta carbonyl acid, reaction with a hydroxylamine compound is carried out to obtain an acyloxyl carbamic acid ester, and under the effect of an alkali, removing of one molecule carbon dioxide is carried out so as to obtain an alpha amino-acid ester, wherein the process of synthesis of the alpha amino-acid ester/amide is similar to the above process. The raw materials are widely available; operation is simple and convenient; reaction conditions are mild; using of toxic cyanide and derivatives of cyanide, strong oxidizing/reducing agents, and precious metal catalysts in a conventional alpha amino acid synthesis method is avoided; and requirements of the trend of green chemistry development are satisfied.
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Paragraph 0070-0071
(2019/10/10)
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- Design and synthesis of novel diamide derivatives of glycine as antihyperglycemic agents
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DPP-4 inhibition is one of the most extensively explored approaches for the management of type 2 diabetes (T2D). Most DPP-4 inhibitors in the market contain a proline mimetic active pharmacophore. Herein, we report the design, synthesis, and preliminary e
- Sharma, Radhika,Soman, Shubhangi S.
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supporting information
p. 1307 - 1317
(2016/08/16)
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- Pharmaceutically Active Pyrazine Derivatives
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The invention provides compounds which inhibit or modulate the activity of Chk-1 kinase and which are useful in the treatment of cancer. The compounds have the general formula (1): and salts, N-oxides and tautomers thereof, wherein m is 2, 3 or 4; n is 0
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Paragraph 0595
(2014/11/11)
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- PHARMACEUTICALLY ACTIVE PYRAZINE DERIVATIVES
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The invention provides compounds which inhibit or modulate the activity of Chk-1 kinase and which are useful in the treatment of cancer. The compounds have the general formula (1) and salts, N-oxides and tautomers thereof, wherein m is 2, 3 or 4; n is 0 o
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Page/Page column 81
(2013/06/05)
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- The aza-[2,3]-Wittig sigmatropic rearrangement of acyclic amines: Scope and limitations of silicon assistance
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The inclusion of a C-2 trialkylsilyl substituent into allylic amine precursors allows the base-induced aza-[2,3]-Wittig sigmatropic rearrangement to proceed in excellent yield and diastereoselectivity. The rearrangement precursors require a carbonyl-based nitrogen protecting group that must be stable to excess of strong base required for the reaction. The N-Boc and N-benzoyl group are very good at stabilizing the product anion and initiating deprotonation. The migrating groups (G) need to stabilize the intial anion by resonance and require G-CH3 pKa > 22 in order for the initial anion to be reactive enough for rearrangement. Products 7, 29b-d,f,g, and 23 are formed with high (10-20:1) anti diastereoselectivity. Product 23 containing the morpholine amide group is useful for preparing other carbonyl derivatives.
- Anderson,Flaherty,Swarbrick
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p. 9152 - 9156
(2007/10/03)
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- Inhibitors of Cyclic AMP Phosphodiesterase. 4. Synthesis and Evaluation of Potential Prodrugs of Lixazinone (N-Cyclohexyl-N-methyl-4quinazolin-7-yl)oxy>butyramide, RS-82856)
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The cyclic AMP phosphodiesterase (cAMP PDE) inhibitor and cardiotonic agent lixazinone (N-cyclohexyl-N-methyl-4-quinazolin-7-yl)oxy>butyramide, RS-82856, 1) and its acid and base addition salts were found to be insufficiently soluble in formulations suitable for intravenous administration.These results prompted an investigation into potential prodrugs with enhanced aqueous solubility designed to deliver 1 by three distinct mechanisms: (1) decarboxylation of α-carboxamides; (2) hydrolytic loss of a solubilizing N-1-(acyloxy)methyl or (N,N-dialkylamino)methyl moiety; or (3) intramolecular closure of a guanidino ester or amide.The target compounds were evaluated as delivery systems for 1 by three criteria: (1) chemical conversion rate to 1 under physiological conditions; (2) inhibition of type IV cAMP PDE at a fixed time point; and (3) in vivo inotropic activity in anesthetized dogs by both intravenous and oral administration.Release of 1 from 4a (series 1) was found to be too slow to be of value as prodrug of 1, since decarboxylation could be induced only by strong acid, conditions under which hydrolytic ring opening was found to severely compete.Conversely, 1 was released too readily on exposure of (N,N-dialkylamino)methyl derivatives such as 8d (series 2) to physiological conditions, although no large increase in aqueous solubility was realized.Finally, both the physicochemical and in vitro studies indicated that ring closure of the guanidinium esters and amides 17a-k (series 3) to 1 was quantitative and pH- and time-dependent, suggesting the possibility of delivery of the open, water-soluble prodrug form, followed by closure to 1 in plasma.Detailed examination of these agents in vivo, however, demonstrated that only those compounds that rapidly cyclized to 1, as measured by plasma levels of 1, exhibited inotropic activity, indicating that the open prodrug form was not efficiently absorbed upon oral administration.
- Venuti, Michael C.,Alvarez, Robert,Bruno, John J.,Strosberg, Arthur M.,Gu, Leo,et al.
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p. 2145 - 2152
(2007/10/02)
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