- Stereocontrolled approach to quinuclidine derivatives
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Asymmetric Michael-type cyclization of chiral enamino ester (S)-7 furnished the quinuclidinone derivative (3R, 4S)-5, with a high degree of stereoselectivity.
- Da Silva Goes, Alexandre J.,Cave, Christian,D'Angelo, Jean
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- Optimization of pyrrolamide topoisomerase II inhibitors toward identification of an antibacterial clinical candidate (AZD5099)
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AZD5099 (compound 63) is an antibacterial agent that entered phase 1 clinical trials targeting infections caused by Gram-positive and fastidious Gram-negative bacteria. It was derived from previously reported pyrrolamide antibacterials and a fragment-based approach targeting the ATP binding site of bacterial type II topoisomerases. The program described herein varied a 3-piperidine substituent and incorporated 4-thiazole substituents that form a seven-membered ring intramolecular hydrogen bond with a 5-position carboxylic acid. Improved antibacterial activity and lower in vivo clearances were achieved. The lower clearances were attributed, in part, to reduced recognition by the multidrug resistant transporter Mrp2. Compound 63 showed notable efficacy in a mouse neutropenic Staphylococcus aureus infection model. Resistance frequency versus the drug was low, and reports of clinical resistance due to alteration of the target are few. Hence, 63 could offer a novel treatment for serious issues of resistance to currently used antibacterials.
- Basarab, Gregory S.,Hill, Pamela J.,Garner, C. Edwin,Hull, Ken,Green, Oluyinka,Sherer, Brian A.,Dangel, P. Brian,Manchester, John I.,Bist, Shanta,Hauck, Sheila,Zhou, Fei,Uria-Nickelsen, Maria,Illingworth, Ruth,Alm, Richard,Rooney, Mike,Eakin, Ann E.
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p. 6060 - 6082
(2014/08/18)
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- PYRIMIDINYL TYROSINE KINASE INHIBITORS
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The present invention provides compounds and compositions thereof which are useful as inhibitors of Bruton's tyrosine kinase and which exhibit desirable characteristics for the same.
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Paragraph 0083
(2014/01/08)
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- The Role of the acidity of N-heteroaryl sulfonamides as inhibitors of Bcl-2 family protein-protein interactions
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Overexpression of the antiapoptotic members of the Bcl-2 family of proteins is commonly associated with cancer cell survival and resistance to chemotherapeutics. Here, we describe the structure-based optimization of a series of N-heteroaryl sulfonamides t
- Touré, B. Barry,Miller-Moslin, Karen,Yusuff, Naeem,Perez, Lawrence,Doré, Michael,Joud, Carol,Michael, Walter,Dipietro, Lucian,Van Der Plas, Simon,McEwan, Michael,Lenoir, Francois,Hoe, Madelene,Karki, Rajesh,Springer, Clayton,Sullivan, John,Levine, Kymberly,Fiorilla, Catherine,Xie, Xiaoling,Kulathila, Raviraj,Herlihy, Kara,Porter, Dale,Visser, Michael
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supporting information
p. 186 - 190
(2013/04/10)
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- PYRROLE DERIVATIVES WITH ANTIBACTERIAL ACTIVITY
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Compounds of formula (I) and their pharmaceutically acceptable salts are described. Processes for their preparation, pharmaceutical compositions containing them, their use as medicaments and their use in the treatment of bacterial infections are also described.
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Page/Page column 93-94
(2008/06/13)
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- Structure-based design and synthesis of macroheterocyclic peptidomimetic inhibitors of the aspartic protease β-site amyloid precursor protein cleaving enzyme (BACE)
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Based on the X-ray cocrystal structure of the Tang-Ghosh heptapeptide inhibitor 1 (OM00-3), a series of macroheterocyclic analogues were designed and synthesized. Analogues containing dithia, dioxa, oxathia, and carbathia macrocycles were synthesized by m
- Hanessian, Stephen,Yang, Gaoqiang,Rondeau, Jean-Michel,Neumann, Ulf,Betschart, Claudia,Tintelnot-Blomley, Marina
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p. 4544 - 4567
(2007/10/03)
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- Design and syntheses of melanocortin subtype-4 receptor agonists. Part 2: Discovery of the dihydropyridazinone motif
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Optimization of the biological activity of a new class of non-peptidyl, pyridazinone derived human melanocortin subtype-4 receptor agonists is disclosed.
- Ujjainwalla, Feroze,Warner, Daniel,Snedden, Christine,Grisson, Ricky D.,Walsh, Thomas F.,Wyvratt, Matthew J.,Kalyani, Rubana N.,MacNeil, Tanya,Tang, Rui,Weinberg, David H.,Van Der Ploeg, Lex,Goulet, Mark T.
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p. 4023 - 4028
(2007/10/03)
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- N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity
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The present application describes modulators of CCR3 of formula (I): or pharmaceutically acceptable salt forms thereof, useful for the prevention of asthma and other allergic diseases.
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- Synthesis of N-methyl-3-acetoxy-4-(1-hydroxy-3-[123I]iodoprop-2-enyl) piperidine, a novel acetylcholine analog
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Lipophilic acetylcholine analogs (N-methylpiperidine derivatives) have been used to map central acetylcholinesterase (AchE) activity in animals and humans. In the former meeting, we reported synthesis of an analog with 4-acetoxy group and side chain at 3-position labeled with iodine-123 (MHIP4A) which showed moderate metabolic clearance. Now, we have synthesized another analog with higher metabolic clearance, namely, N-methyl-3-acetoxy-4-(1-hydroxy-3-[123I]iodoprop-2-enyl)piperidine (HIP3C3A). Eight isomers of HIP3C3A were isolated by diastereomeric and enantiomeric separation with silica gel chromatography and chiralcel HPLC. Tributylstannyl precursors were used for iodination with peracetic acid as an oxidizing agent. The iodination could be carried out quite easily yielding 50-60%. Of the isomers, one isomer showed extremely high metabolic clearance (4.19 mL/min/g with 84% specificity) and another isomer was hydrolyzed by AchE moderately (0.36 mL/min/g with 95% specificity) in rat cerebral cortical homogenate.
- Ueda,Irie,Fukushi,Ikota,Namba,Shinotoh,Iyo,Tanada,Maeda,Takatoku,Yomoda,Nagatsuka
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p. S762-S764
(2007/10/03)
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