A novel series of non-imidazole bicyclic and tricyclic histamine H3 receptor antagonists has been discovered. Compound 17 was identified as a centrally penetrant molecule with high receptor occupancy ...which demonstrates robust oral activity in rodent models of obesity. In addition compound 17 possesses clean CYP and hERG profiles and shows no behavioral changes in the Irwin test.
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Structure−activity relationship (SAR) studies by modification of the unsaturated side chain of potent anticancer marine natural product psymberin/irciniastatin A (1) suggest that substitution at C4 ...and C5 is important for the cytotoxicity of psymberin, but the terminal double bond is not essential for activity. An aryl group is a good replacement for the olefin. The total synthesis of structurally simplified C11-deoxypsymberin (29) was completed, and its activity is consistently more potent than the natural product which provides a unique opportunity for further SAR studies in the psymberin and pederin family. Preliminary mechanism studies suggest the mode of action of psymberin is through cell apoptosis.
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4.
Discovery of oral and inhaled PDE4 inhibitors Ting, Pauline C.; Lee, Joe F.; Kuang, Rongze ...
Bioorganic & medicinal chemistry letters,
10/2013, Volume:
23, Issue:
20
Journal Article
Peer reviewed
The optimization of oxazole-based PDE4 inhibitor 1 has led to the identification of both oral (compound 16) and inhaled (compound 34) PDE4 inhibitors. Selectivity against PDE10/PDE11, off target ...screening, and in vivo activity in the rat are discussed.
The optimization of oxazole-based PDE4 inhibitor 1 has led to the identification of both oral (compound 16) and inhaled (compound 34) PDE4 inhibitors. Selectivity against PDE10/PDE11, off target screening, and in vivo activity in the rat are discussed.
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Herein we report the design and synthesis of a series of novel bicyclic DGAT1 inhibitors with a carboxylic acid moiety. The optimization of the initial lead compound 7 based on in vitro and in vivo ...activity led to the discovery of potent indoline and quinoline classes of DGAT1 inhibitors. The structure–activity relationship studies of these novel series of bicyclic carboxylic acid derivatives as DGAT1 inhibitors are described.
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Learn why some drug discovery and development efforts succeed . . . and others fail Written by international experts in drug discovery and development, this book sets forth carefully researched and ...analyzed case studies of both successful and failed drug discovery and development efforts, enabling medicinal chemists and pharmaceutical scientists to learn from actual examples. Each case study focuses on a particular drug and therapeutic target, guiding readers through the drug discovery and development process, including drug design rationale, structure-activity relationships, pharmacology, drug metabolism, biology, and clinical studies.Case Studies in Modern Drug Discovery and Developmentbegins with an introductory chapter that puts into perspective the underlying issues facing the pharmaceutical industry and provides insight into future research opportunities. Next, there are fourteen detailed case studies, examining:All phases of drug discovery and development from initial idea to commercializationSome of today's most important and life-saving medicationsDrugs designed for different therapeutic areas such as cardiovascular disease, infection, inflammation, cancer, metabolic syndrome, and allergiesExamples of prodrugs and inhaled drugsReasons why certain drugs failed to advance to market despite major research investmentsEach chapter ends with a list of references leading to the primary literature. There are also plenty of tables and illustrations to help readers fully understand key concepts, processes, and technologies.Improving the success rate of the drug discovery and development process is paramount to the pharmaceutical industry. With this book as their guide, readers can learn from both successful and unsuccessful efforts in order to apply tested and proven science and technologies that increase the probability of success for new drug discovery and development projects.
A unified strategy was conceived and implemented to deliver conformationally constrained anilides based on their preferred cis-amide conformers. The imidazole/triazole mimicing amide bonds were ...designed, building upon an earlier discovery of a novel series of tricyclic lactams MK2 kinase inhibitors. This approach enabled rapid, modular synthesis of structurally novel analogs. The efficient SAR development led to the discovery of low molecular weight and potent MK2 non-ATP competitive inhibitors with good ligand efficiency, which led to improved permeability and oral exposure in rats.
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A novel series of benzimidazolone-containing histamine H3-receptor antagonists were prepared and their structure–activity relationship was explored. These benzimidazolone analogs demonstrate potent ...H3-receptor binding affinities, no P450 enzyme inhibition, and strong H3 functional activity. Compound 1o exhibits the best overall profile with H3Ki=0.95nM and rat AUC=12.9μMh.
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A series of 2-(1,4'-bipiperidine-1'-yl)thiazolopyridines was synthesized and evaluated as a new lead of non-imidazole histamine H(3) receptor antagonists. Introduction of diversity at the 6-position ...of the pyridine ring was designed to enhance in vitro potency and decrease hERG activity. The structure-activity relationships for these new thiazolopyridine antagonists are discussed.
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The structure–activity relationship studies of a novel series of carboxylic acid derivatives of pyridine-carboxamides as DGAT-1 inhibitors is described. The optimization of the initial lead compound ...6 based on in vitro and in vivo activity led to the discovery of key compounds 10j and 17h.
The structure–activity relationship studies of a novel series of carboxylic acid derivatives of pyridine-carboxamides as DGAT-1 inhibitors is described. The optimization of the initial lead compound 6 based on in vitro and in vivo activity led to the discovery of key compounds 10j and 17h.
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