- BENZOXAZINONE DERIVATIVES AND ANALOGUES THEREOF AS MODULATORS OF TNF ACTIVITY
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A series of substituted 3,4-dihydro-2H-.1,4-benzoxazin-3-one derivatives, and analogues thereof, being potent modulators of human TNFa activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune
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Page/Page column 62
(2016/12/26)
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- Structure activity relationship of pyridoxazinone substituted RHS analogs of oxabicyclooctane-linked 1,5-naphthyridinyl novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents (Part-6)
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Abstract Oxabicyclooctane linked 1,5-naphthyridinyl-pyridoxazinones are novel broad-spectrum bacterial topoisomerase inhibitors (NBTIs) targeting bacterial DNA gyrase and topoisomerase IV at a site different than quinolones. Due to lack of cross-resistance to known antibiotics they present excellent opportunity to combat drug-resistant bacteria. A structure activity relationship of the pyridoxazinone moiety is described in this Letter. Chemical synthesis and activities of NBTIs with substitutions at C-3, C-4 and C-7 of the pyridoxazinone moiety with halogens, alkyl groups and methoxy group has been described. In addition, substitutions of the linker NH proton and its transformation into amide analogs of AM-8085 and AM-8191 have been reported. Fluoro, chloro, and methyl groups at C-3 of the pyridoxazinone moiety retained the potency and spectrum. In addition, a C-3 fluoro analog showed 4-fold better oral efficacy (ED50 3.9 mg/kg) as compared to the parent AM-8085 in a murine bacteremia model of infection of Staphylococcus aureus. Even modest polarity (e.g., methoxy) is not tolerated at C-3 of the pyridoxazinone unit. The basicity and NH group of the linker is important for the activity when CH2 is at the linker position-8. However, amides (with linker position-8 ketone) with a position-7 NH or N-methyl group retained potency and spectrum suggesting that neither basicity nor hydrogen-donor properties of the linker amide NH is essential for the activity. This would suggest likely an altered binding mode of the linker position-7,8 amide containing compounds. The amides showed highly improved hERG (functional IC50 >30 μM) profile.
- Singh, Sheo B.,Kaelin, David E.,Wu, Jin,Miesel, Lynn,Tan, Christopher M.,Meinke, Peter T.,Olsen, David B.,Lagrutta, Armando,Wei, Changqing,Liao, Yonggang,Peng, Xuanjia,Wang, Xiu,Fukuda, Hideyuki,Kishii, Ryuta,Takei, Masaya,Yajima, Masanobu,Shibue, Taku,Shibata, Takeshi,Ohata, Kohei,Nishimura, Akinori,Fukuda, Yasumichi
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p. 3636 - 3643
(2015/08/06)
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- BICYCLIC PYRIDINES AND ANALOGS AS SIRTUIN MODULATORS
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Provided herein are novel sirtuin-modulating compounds and methods of use thereof. The sirtuin-modulating compounds may be used for increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity. Also provided are compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.
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Page/Page column 85
(2011/06/16)
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- 3-pyridyloxymethyl heterocyclic ether compounds useful in controlling neurotransmitter release
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Novel heterocyclic ether compounds of the formula: STR1 wherein n, *, R1, R2, R3 and y are specifically defined, or pharmaceutically acceptable salts or prodrugs thereof, which are useful in selectively controlling neurotransmitter release; therapeutically-effective pharmaceutical compositions of these compounds; and use of said compositions to selectively control neurotransmitter release in mammals.
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- Antiulcer Agents. 2. Gastric Antisecretory, Cytoprotective, and Metabolic Properties of Substituted Imidazolpyridines and Analogues
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The search for a successor to 3-(cyanomethyl)-2-methyl-8-(phenylmethoxy)imidazopyridine, Sch 28080 (27), a compound that exhibits gastric antisecretory and cytoprotective properties and has undergone clinical evaluation as an antiulcer agent, has culminated in the identification of four related compounds that exhibit pharmacologic profiles similar to that of 27.In three of these potential successors an amino group functions as a surrogate for the 3-cyanomethyl substituent of the prototype.The present work concerns, in addition to an evaluation of the structure-activity relationships of a series of analogues of 27, preliminary studies of the pharmacodynamics and metabolism of 27, performed with the aid of cyano carbon labeled versions of the drug (13C labeled; 28; 14C labeled, 29).These studies have shown that 27 is well-absorbed and extensively metabolized and that the major metabolite of 27 is the thiocyanate anion.A similar study performed on 3-amino-2-methyl-8-(phenylmethoxy)imidazopyridine, labeled at the 3-position with carbon-13 (41) or carbon-14 (42), revealed that this compound, which has an antisecretory/cytoprotective profile comparable to that of 27, is also metabolized to thiocyanate anion, although this must occur via a different mechanism.The chemistry section includes a discussion of the potential sites of protonation of the pharmacologically similar 3-amino analogue 40 and the structurally related imidazopyrazine 67.Predictions based on charge density and protonation product stabilities are presented.That N1 is the site of protonation in these analogues has been definitively demonstrated by X-ray crystal structure analysis, which alsounequivocally established the assigned imidazopyrazine ring structure.
- Kaminski, James J.,Hilbert, James M.,Pramanik, B. N.,Solomon, Daniel M.,Conn, David J.,et al.
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p. 2031 - 2046
(2007/10/02)
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- Synthesis of 4-Alkyl-3-pyridinols from 3-Benzyloxypyridine
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The addition of Grignard reagents to the 1-phenoxycarbonyl salt of 3-benzyloxypyridine and a catalytic amount of cuprous iodide afforded 4-alkyl-3-benzyloxy-1-phenoxycarbonyl-1,4-dihydropyridines in good yield.The crude dihydropyridines were aromatized wi
- Comins, Daniel L.,Stroud, Eric D.
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p. 1419 - 1420
(2007/10/02)
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- Directed Ortho Metalation of O-Pyridyl Carbamates. Regiospecific Entries into Polysubstituyed Pyridines
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Ortho-lithiated species of O-pyridyl carbamates 1a-c constitute new synthetic intermediates which provide a variety of polysubstituted pyridines (Table I) by reaction with electrophiles (2a-c) and anionic Fries rearrangement (3,4).Further metalation (7), ipso carbodestannylation (10, E=I, COMe), and reductive elimination of the carbamate directing group (56) are also described.
- Miah, M. A. J.,Snieckus, V.
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p. 5436 - 5438
(2007/10/02)
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