- Inhibition of 1-deoxy-d-xylulose-5-phosphate reductoisomerase by lipophilic phosphonates: SAR, QSAR, and crystallographic studies
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1-Deoxy-d-xylulose-5-phosphate reductoisomerase (DXR) is a novel target for developing new antibacterial (including antituberculosis) and antimalaria drugs. Forty-one lipophilic phosphonates, representing a new class of DXR inhibitors, were synthesized, among which 5-phenylpyridin-2-ylmethylphosphonic acid possesses the most activity against E. coli DXR (EcDXR) with a K i of 420 nM. Structure-activity relationships (SAR) are discussed, which can be rationalized using our EcDXR:inhibitor structures, and a predictive quantitative SAR (QSAR) model is also developed. Since inhibition studies of DXR from Mycobacterium tuberculosis (MtDXR) have not been performed well, 48 EcDXR inhibitors with a broad chemical diversity were found, however, to generally exhibit considerably reduced activity against MtDXR. The crystal structure of a MtDXR:inhibitor complex reveals the flexible loop containing the residues 198-208 has no strong interactions with the 3,4-dichlorophenyl group of the inhibitor, representing a structural basis for the reduced activity. Overall, these results provide implications in the future design and development of potent DXR inhibitors.
- Deng, Lisheng,Diao, Jiasheng,Chen, Pinhong,Pujari, Venugopal,Yao, Yuan,Cheng, Gang,Crick, Dean C.,Prasad, B. V. Venkataram,Song, Yongcheng
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p. 4721 - 4734
(2011/09/19)
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- PYRIDINE DERIVATIVE SUBSTITUTED BY HETEROARYL RING, AND ANTIFUNGAL AGENT COMPRISING THE SAME
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The present invention provides an antifungal agent that has excellent antifungal action, and is also excellent in terms of its properties, safety, and metabolic stability. The present invention discloses a compound represented by the following formula I or a salt thereof, and an antifungal agent comprising the compound or the salt: wherein R1 represents a hydrogen atom, a halogen atom, an amino group, a C1-6 alkyl group, a C1-6 alkoxy group, or a C1-6-alkoxy-C1-6-alkyl group; R2 represents a hydrogen atom or an amino group; X, Y, Z, and W independently represent a nitrogen atom, an oxygen atom, a sulfur atom, or -CH-, provided that at least two among X, Y, and W are nitrogen atoms; the ring A represents a 5- or 6-membered heteroaryl ring or a benzene ring; Q represents a methylene group, an oxygen atom, -CH2O-, -OCH2-, -NH-, -NHCH2-, or -CH2NH-; and R3 represents a C1-6 alkyl group, a C3-8 cycloalkyl group, a C6-10 aryl group, or a 5- or 6-membered heteroaryl group, each of which may have one or two substituents.
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Page/Page column 95
(2009/06/27)
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- Pyridine-2-propanoic acids: Discovery of dual PPARα/γ agonists as antidiabetic agents
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A series of novel pyridine-2-propanoic acids was synthesized. A structure-activity relationship study of these compounds led to the identification of potent dual PPARα/γ agonists with varied isoform selectivity. Based on the results of efficacy studies in
- Humphries, Paul S.,Almaden, Jonathon V.,Barnum, Sandra J.,Carlson, Thomas J.,Do, Quyen-Quyen T.,Fraser, James D.,Hess, Mary,Kim, Young H.,Ogilvie, Kathleen M.,Sun, Shaoxian
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p. 6116 - 6119
(2008/12/20)
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- ALPHA SUBSTITUTED CARBOXYLIC ACID AS PPAR MODULATORS
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Alpha substituted carboxylic acids of formula (I): wherein R' and R2 are as defined in the specification and R3 is A) formula (II); B) formula (III); C) formula (IV); and D) formula (V); wherein Y, Art, Are, AP, R4, R5, R6, R7, R6, R9, R9a, R10, R", R12, R17, ring A, and p are as defined in the specification; pharmaceutical compositions containing effective amounts of said compounds or their salts are useful for treating PPAR, specifically PPAR α/y related disorders, such as diabetes, dyslipidemia, obesity and inflammatory disorders.
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- New κ-Receptor Agonists Based upon a 2-piperidine Nucleus
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The syntheses of some 1--2-piperidines and their activities as κ-opioid receptor agonists are described.Selected structural modifications are made to the basic moiety and at the 2-, 3-, 4-, 5-, and 6-positions on the piperidine nucleus to enable structure-activity relationships to be delineated.As a result, some highly potent and selective κ-receptor agonists have been identified.In particular, this has been achieved by introduction of oxygen-containing functionality into the 4-position of the piperidine nucleus or the 3-position of the pyrrolidinylmethyl side chain.Thus, 1--2-piperidine (10) possesses high activity in the rabbit vas deferens (LVD, κ-specific tissue) (IC50 = 0.20 nM) and is a potent antinociceptive agent, as determined by the mouse acetylcholine-induced abdominal constriction test (MAC) (ED50 = 0.06 mg/kg, sc).The spirocyclic analogue 8--7-(1-pyrrolidinylmethyl)-1,4-dioxa-8-azaspirodecane (39) showed exceptionally potent activity: LVD, IC50 = 0.10 nM; MAC, ED50 = 0.001 mg/kg, sc.Both 10 and 39 displayed high selectivity for κ-opioid receptors over both μ- and δ-opioid receptor subtypes.
- Scopes, David I. C.,Hayes, Norman F.,Bays, David E.,Belton, David,Brain, John,et al.
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p. 490 - 501
(2007/10/02)
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