- Development and preclinical evaluation of new inhaled lipoglycopeptides for the treatment of persistent pulmonary methicillin-resistant staphylococcus aureus infections
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Chronic pulmonary methicillin-resistant Staphylococcus aureus (MRSA) disease in cystic fibrosis (CF) has a high probability of recurrence following treatment with standard-of-care antibiotics and represents an area of unmet need associated with reduced life expectancy. We developed a lipoglycopeptide therapy customized for pulmonary delivery that not only demonstrates potent activity against planktonic MRSA, but also against protected colonies of MRSA in biofilms and within cells, the latter of which have been linked to clinical antibiotic failure. A library of next-generation potent lipoglycopeptides was synthesized with an emphasis on attaining superior pharmacokinetics (PK) and pharmacodynamics to similar compounds of their class. Our strategy focused on hydrophobic modification of vancomycin, where ester and amide functionality were included with carbonyl configuration and alkyl length as key variables. Candidates representative of each carbonyl attachment chemistry demonstrated potent activity in vitro, with several compounds being 30 to 60 times more potent than vancomycin. Selected compounds were advanced into in vivo nose-only inhalation PK evaluations in rats, where RV94, a potent lipoglycopeptide that utilizes an inverted amide linker to attach a 10-carbon chain to vancomycin, demonstrated the most favorable lung residence time after inhalation. Further in vitro evaluation of RV94 showed superior activity to vancomycin against an expanded panel of Gram-positive organisms, cellular accumulation and efficacy against intracellular MRSA, and MRSA biofilm killing. Moreover, in vivo efficacy of inhaled nebulized RV94 in a 48 h acute model of pulmonary MRSA (USA300) infection in neutropenic rats demonstrated statistically significant antibacterial activity that was superior to inhaled vancomycin.
- Plaunt, Adam J.,Rose, Sasha J.,Kang, Jeong Yeon,Chen, Kuan-Ju,LaSala, Daniel,Heckler, Ryan P.,Dorfman, Arielle,Smith, Barrett T.,Chun, Donald,Viramontes, Veronica,Macaluso, Antonio,Li, Zhili,Zhou, Yuchen,Mark, Lilly,Basso, Jessica,Leifer, Franziska G.,Corboz, Michel R.,Chapman, Richard W.,Cipolla, David,Perkins, Walter R.,Malinin, Vladimir S.,Konicek, Donna M.
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supporting information
(2021/06/22)
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- LIPO-GLYCOPEPTIDE CLEAVABLE DERIVATIVES AND USES THEREOF
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The present invention provides certain lipo-glycopeptide cleavable derivatives and methods for using the same for the treatment of bacterial infections, for example, pulmonary bacterial infections. The LGPC derivatives include a cleavable moiety that in certain embodiments, is designed to allow for cellular uptake and/or a more rapid clearance of the glycopeptide metabolite (i.e., the cleaved glycopeptide) from the site of administration (e.g., the lung) as compared to the uncleaved LGPC. The bacterial infection can comprise intracellular bacteria, planktonic bacteria, bacteria present in a biofilm, or a combination thereof.
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Paragraph 233; 234
(2020/06/10)
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- Synthesis and SAR studies of neuritogenic gentiside derivatives
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Tetradecyl 2,3-dihydroxybenzoate (ABG-001) has been designed and synthesised as a lead compound to treat Alzheimer's disease, based on structure-activity relationships of gentisides. In this paper, the alkyl chain and ester linkage group of ABG-001 were modified. Consequently, several series of novel gentiside derivatives were designed and synthesised, and their neuritogenic activity was evaluated in PC12 cells. Among all the tested compounds, S-dodecyl 2,3-dihydroxybenzothioate (15d, named as ABG-199) was the most potent; the compound induced significant neurite outgrowth at 0.1 μM, which was comparable to that of nerve growth factor at the optimal concentration of 40 ng/mL and ABG-001 at 1 μM. A brief study on the mechanism of action of ABG-199 revealed that extracellular signal-regulated kinase phosphorylation was involved in ABG-199-induced neurite outgrowth in PC12 cells.
- Wang, Guangfa,Bian, Linglin,Zhang, Hui,Wang, Yanhui,Gao, Lijuan,Sun, Kaiyue,Xiang, Lan,Qi, Jianhua
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p. 161 - 170
(2016/02/23)
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- Facile and efficient synthesis of hydroxyalkyl esters from cyclic acetals through aerobic photo-oxidation using anthraquinone-2-carboxylic acid
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Abstract A convenient metal-free oxidation protocol of various cyclic acetals with molecular oxygen and anthraquinone-2-carboxylic acid under visible light irradiation by a fluorescent lamp afforded their corresponding hydroxyalkyl esters.
- Yamaguchi, Tomoaki,Kudo, Yasuhisa,Hirashima, Shin-ichi,Yamaguchi, Eiji,Tada, Norihiro,Miura, Tsuyoshi,Itoh, Akichika
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p. 1973 - 1975
(2015/03/18)
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- PROPOFOL PHOSPHONYL DERIVATIVES, SYNTHESIS, AND USE IN LONG ACTING FORMULATIONS
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This invention relates to compounds represented by the structural formula (I), and the salts and stereoisomers thereof, wherein: - L is a linker selected from the group consisting of -(CH2)P-O-, a single bond, formula (IA), -(CH2)1-8-O-X(O)-, and - p is an integer from 1 to 8, - each R3 and each R4 is independently selected from the group consisting of C1-20alkyl, C3-12alkyl, C3-12cycloalkyl-C1-4alkyl, saturated heterocyclyl and saturated heterocyclyl-C1-4alkyl, and - X and Y are each independently C or S(O), - Z is selected from the group consisting of O, S(O) and NR5, - W is selected from the group consisting of halogen, OH, S(O)H and O-M+ wherein M+ is a monovalent cation; and - R5 is selected from the group consisting of hydrogen and C1-10 alkyl. These compounds are useful pharmaceutical agents with improved oral bioavailability.
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Page/Page column 23
(2010/11/03)
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- Combinatorial synthesis of PEG oligomer libraries
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A simple chain-extending approach was established for the scale-up of the monoprotected monodisperse PEG diol materials. Reactions of THP-(OCH2CH2)n—OMs (n=4, 8, 12) with a large excess of commercially available H—(OCH2CH2)n—OH (n=1-4) under basic conditions led to THP-(OCH2CH2)n—OH (n=5-15). Similarly, Me-(OCH2CH2)n—OH (n=4-11, 13) were prepared from Me-(OCH2CH2)n—OMs (n=3, 7, 11). For the chain elongation steps, 40-80% yields were achieved through extraction purification. PEG oligomer libraries I and II were generated in 50-95% overall yields by alkylation or acylation of THP-(OCH2CH2)n—OH (n=1-15) followed by deprotection. Alkylation of Me-(OCH2CH2)n—OH (n=1-11, 13) with X—(CH2)m—CO2R (X=Br or OMs) and subsequent hydrolysis led to PEG oligomer library III in 30-60% overall yields. Combinatorial purification techniques were adapted to the larger-scale library synthesis. A total of 498 compounds, each with a weight of 2-5 g and a minimum purity of 90%, were synthesized.
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Page/Page column 6
(2010/02/15)
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- PROSTAGLANDIN DERIVATIVES
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Prostaglandin E, ester derivatives of the formula (I) and cyclodextrin clathrates thereof, liposome formulations containing them, and pharmaceutical compositions containing them as active ingredient The compounds of formula (I) have the effect of increasing blood flow and are useful for the prevention and or treatment of peripheral circulatory disorder, decubitus, or skin ulcers, or for the maintenance of blood flow.
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- Conversion of Ketals to Ketones by Nitrogen Dioxide in the Presence of Silica Gel
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Nitrogen dioxide transforms ketals to ketones in the presence of silica gel under neutral, anhydrous and mild conditions.
- Nishiguchi, Takeshi,Ohosima, Tatsuya,Nishida, Akiko,Fujisaki, Shizuo
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p. 1121 - 1122
(2007/10/02)
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- Photoinduced Molecular Transformations. Part 113. One-step Transformations of Cyclic Ethers into ω-Iodoalkyl Formates and of Aldehyde Cyclic Acetals into Monoesters of α,ω-Alkanediols by Iodoxyl Radical
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The reaction of cyclic ethers with iodoxyl radical and iodine oxide gives the corresponding ω-iodoalkyl formates in one step; tetrahydrofuran can be transformed into ω-iodoalkyl formate in 31percent yield.Aldehyde cyclic acetals under conditions similar to the reaction of cyclic ethers lead to monoesters of α,ω-alkanediols in one step; cyclohexanecarboxaldehyde ethylene acetal gives 2-hydroxy cyclohexanecarboxylate in 60percent yield.The pathways leading to ω-iodoalkyl formatesand monoesters of α,ω-alkanediols are discussed based on the results of 18O-labelling studies with (18)OI and I2(18)O.
- Suginome, Hiroshi,Wang, Jian Bo
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p. 2825 - 2829
(2007/10/02)
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