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991.
Brian C. Shook Stefanie Rassnick Daniel Hall Kenneth C. Rupert Geoffrey R. Heintzelman Kristen Hansen Devraj Chakravarty James L. Bullington Robert H. Scannevin Brian Magliaro Lori Westover Karen Carroll Lisa Lampron Ronald Russell Shawn Branum Kenneth Wells Sandra Damon Scott Youells Xun Li Mel Osbourne Paul F. Jackson 《Bioorganic & medicinal chemistry letters》2010,20(9):2864-2867
A novel series of arylindenopyrimidines were identified as A2A and A1 receptor antagonists. The series was optimized for in vitro activity by substituting the 8- and 9-positions with methylene amine substituents. The compounds show excellent activity in mouse models of Parkinson’s disease when dosed orally. 相似文献
992.
Jiaqiang Cai D. Jonathan Bennett Zoran Rankovic Maureen Dempster Xavier Fradera Jonathan Gillespie Iain Cumming William Finlay Mark Baugh Sylviane Boucharens John Bruin Kenneth S. Cameron William Hamilton Jennifer Kerr Emma Kinghorn George McGarry John Robinson Paul Scullion Joost C.M. Uitdehaag Mario van Zeeland Eric Nicolai 《Bioorganic & medicinal chemistry letters》2010,20(15):4447-4450
Starting from previously disclosed equally potent cathepsin K and S inhibitor 4-propyl-6-(3-trifluoromethylphenyl)pyrimidine-2-carbonitrile 1, a novel 2-phenyl-9H-purine-6-carbonitrile scaffold was identified to provide potent and selective cathepsin S inhibitors. 相似文献
993.
Tricyclic dihydroquinazolinones as novel 5-HT2C selective and orally efficacious anti-obesity agents
Saleem Ahmad Khehyong Ngu Keith J. Miller Ginger Wu Chen-pin Hung Sarah Malmstrom Ge Zhang Eva O’Tanyi William J. Keim Mary Jane Cullen Kenneth W. Rohrbach Michael Thomas Thao Ung Qinling Qu Jinping Gan Rangaraj Narayanan Mary Ann Pelleymounter Jeffrey A. Robl 《Bioorganic & medicinal chemistry letters》2010,20(3):1128-1133
Agonists of the 5-HT2C receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT2B receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and highly selective dihydroquinazolinone-derived 5-HT2C agonists with no detectable agonism of the 5-HT2B receptor is described. Among these, compounds (+)-2a and (+)-3c were identified as potent and highly selective agonists which exhibited weight loss in a rat model upon oral dosing. 相似文献
994.
Jiaqiang Cai Mark Baugh Darcey Black Clive Long D. Jonathan Bennett Maureen Dempster Xavier Fradera Jonathan Gillespie Fiona Andrews Sylviane Boucharens John Bruin Kenneth S. Cameron Iain Cumming William Hamilton Philip S. Jones Allard Kaptein Emma Kinghorn Maurice Maidment Iain Martin Ann Mitchell Tommi Meulemans 《Bioorganic & medicinal chemistry letters》2010,20(15):4350-4354
6-Phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile analogues were identified as potent and selective cathepsin S inhibitor against both purified enzyme and in human JY cell based cellular assays. This core has a very stable thio-trapping nitrile war-head in comparison with the well reported pyrimidine-2-carbonitrile cysteine cathepsin inhibitors. Compound 47 is also very potent in in vivo mouse spleenic Lip10 accumulation assays. 相似文献
995.
Bidhan A. Shinkre T. Santhosh Kumar Zhan-Guo Gao Francesca Deflorian Kenneth A. Jacobson William C. Trenkle 《Bioorganic & medicinal chemistry letters》2010,20(19):5690-5694
Movement disorders such as Parkinson’s disease and Huntington’s disease are serious life-limiting and debilitating movement disorders. Their onset typically occurs from mid-life to late in life, and effective diagnostic techniques for detecting and following the disease course are lacking. Our goal is to develop receptor imaging agents for positron emission tomography (PET) that selectively target the most relevant subtype of adenosine receptors (AR) that are highly expressed in the striatum, that is, the A2A AR. To further this goal, we have synthesized and characterized pharmacologically a family of high affinity A2A AR ligands, based on the known antagonist, SCH 442416 (R = –Me), which have structural variability on the terminus (R = –Et, –i-Pr, –allyl, and others). A O-fluoroethyl analogue suitable for use as a PET tracer had a Ki value of 12.4 nM and was highly selective for the A2A AR in comparison to the A1 and A3 ARs. 相似文献
996.
Chiao-Ting Yen Kyoko Nakagawa-Goto Tsong-Long Hwang Pei-Chi Wu Susan L. Morris-Natschke Wan-Chun Lai Kenneth F. Bastow Fang-Rong Chang Yang-Chang Wu Kuo-Hsiung Lee 《Bioorganic & medicinal chemistry letters》2010,20(3):1037-1039
The first total synthesis of the naturally occurring tetracyclic homoisoflavonoid brazilein (1) and 14 new analogs (1a–n) is reported. Target compounds and intermediates were assayed for anti-inflammatory effects on superoxide anion generation and elastase release by human neutrophils in response to fMLP/CB, and for cytotoxic activity against nasopharyngeal (KB), vincristine-resistant nasopharyngeal (KBvin), lung (A549) and prostate (DU-145) human cancer cell lines. The most active compound 1b showed potent effects on superoxide anion generation and elastase release with IC50 values of 1.2 and 1.9 μM, respectively, and was 65 times more potent than phenylmethylsulfonyl fluoride (PMSF), the positive control, in the latter assay. Additionally, 1b exhibited broad spectrum in vitro anticancer activity with IC50 values of 6–11 μM against the four tested cancer cell lines. 相似文献
997.
Haifeng Tang Yan Yan Zhe Feng Reynalda K. de Jesus Lihu Yang Dorothy A. Levorse Karen A. Owens Taro E. Akiyama Raynald Bergeron Gino A. Castriota Thomas W. Doebber Kenneth P. Ellsworth Michael E. Lassman Cai Li Margaret S. Wu Bei B. Zhang Kevin T. Chapman Sander G. Mills Joel P. Berger Alexander Pasternak 《Bioorganic & medicinal chemistry letters》2010,20(20):6088-6092
A new series of thiazole-substituted 1,1,1,3,3,3-hexafluoro-2-propanols were prepared and evaluated as malonyl-CoA decarboxylase (MCD) inhibitors. Key analogs caused dose-dependent decreases in food intake and body weight in obese mice. Acute treatment with these compounds also led to a drop in elevated blood glucose in a murine model of type II diabetes. 相似文献
998.
Feng V. Yang William D. Shipe Jaime L. Bunda M. Brad Nolt David D. Wisnoski Zhijian Zhao James C. Barrow William J. Ray Lei Ma Marion Wittmann Matthew A. Seager Kenneth A. Koeplinger George D. Hartman Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2010,20(2):531-536
An iterative analog library synthesis approach was employed in the exploration of a quinolone carboxylic acid series of selective M1 positive allosteric modulators, and strategies for improving potency and plasma free fraction were identified. 相似文献
999.
Xiang-Yang Ye Stephanie Chen Hao Zhang Kenneth T. Locke Kevin O’Malley Litao Zhang Raijit Srivastava Bowman Miao Daniel Meyers Hossain Monshizadegan Debra Search Denise Grimm Rongan Zhang Jonathan Lippy Celeste Twamley Jodi K. Muckelbauer Chiehying Chang Yongmi An Vinayak Hosagrahara Lisa Zhang Joseph A. Tino 《Bioorganic & medicinal chemistry letters》2010,20(9):2933-2937
The synthesis and follow-up SAR studies of our development candidate 1 by incorporating 2-aryl-4-oxazolylmethoxy and 2-aryl-4-thiazolylmethoxy moieties into the oxybenzylglycine framework of the PPARα/γ dual agonist muraglitazar is described. SAR studies indicate that different substituents on the aryloxazole/thiazole moieties as well as the choice of carbamate substituent on the glycine moiety can significantly modulate the selectivity of PPARα versus PPARγ. Potent, highly selective PPARα activators 2a and 2l, as well as PPARα activators with significant PPARγ activity, such as 2s, were identified. The in vivo pharmacology of these compounds in preclinical animal models as well as their ADME profiles are discussed. 相似文献
1000.
Min Zhong Wang Shen Kenneth J. Barr Jennifer P. Arbitrario Michelle R. Arkin Minna Bui Teresa Chen Brian C. Cunningham Marc J. Evanchik Emily J. Hanan Ute Hoch Karen Huen Jennifer Hyde Jeffery L. Kumer Teresa Lac Chris E. Lawrence Jose R. Martell Johan D. Oslob Kumar Paulvannan Saileta Prabhu W. Mike Flanagan 《Bioorganic & medicinal chemistry letters》2010,20(17):5269-5273
This letter describes the discovery of a novel series of tetrahydroisoquinoline (THIQ)-derived small molecules that potently inhibit both human T-cell migration and super-antigen induced T-cell activation through disruption of the binding of integrin LFA-1 to its receptor, ICAM-1. In addition to excellent in vitro potency, 6q shows good pharmacokinetic properties and its ethyl ester (6t) demonstrates good oral bioavailability in both mouse and rat. Either intravenous administration of 6q or oral administration of its ethyl ester (6t) produced a significant reduction of neutrophil migration in a thioglycollate-induced murine peritonitis model. 相似文献