- Discovery of Novel Small Molecule Dual Inhibitors Targeting Toll-Like Receptors 7 and 8
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Endosomal toll-like receptors (TLRs) 7 and 8 recognize viral single-stranded RNAs, a class of imidazoquinoline compounds, 8-oxo-adenosines, 8-aminobenzodiazepines, pyrimidines, and guanosine analogues. Substantial evidence is present linking chronic inflammation mediated specifically by TLR7 to the progression of autoimmunity. We identified a new TLR7/8 dual inhibitor (1) and a TLR8-specific inhibitor (2) based on our previous screen targeting TLR8. Compound 1, bearing a benzanilide scaffold, was found to inhibit TLR7 and TLR8 at low micromolar concentrations. We envisioned making modifications on the benzanilide scaffold of 1 resulting in a class of highly specific TLR7 inhibitors. Our efforts led to the discovery of a new TLR8 inhibitor (CU-115) and identification of a TLR7/8 dual inhibitor (CU-72), bearing a distinct diphenyl ether skeleton, with potential for TLR7 selectivity optimization. Given the role of TLR8 in autoimmunity, we also optimized the potency of 2 and developed a new TLR8 inhibitor bearing a 1,3,4-oxadiazole motif.
- Padilla-Salinas, Rosaura,Anderson, Rachel,Sakaniwa, Kentaro,Zhang, Shuting,Nordeen, Patrick,Lu, Chuanjun,Shimizu, Toshiyuki,Yin, Hang
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p. 10221 - 10244
(2019/11/29)
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- DIPHENYL SUBSTITUTED ALKANES
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The instant invention provides compounds of Formula I which are 5-lipoxygenase activating protein inhibitors: formula (I). Compounds of Formula I are useful as anti-atherosclerotic, anti-asthmatic, anti-allergic, anti-inflammatory and cytoprotective agents.
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Page/Page column 60
(2009/01/23)
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- BICYCLIC HETEROARYL COMPOUNDS AS PDE10 INHIBITORS
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The invention pertains to bicyclic heteroaryl compounds that serve as effective phosphodiesterase (PDE) inhibitors The invention also relates to compounds which are selective inhibitors of PDE-10. The invention further relates to intermediates for prepara
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Page/Page column 26
(2010/11/27)
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- Heteroaromatic quinoline compounds
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The invention pertains to heteroaromatic compounds that serve as effective phosphodiesterase (PDE) inhibitors. In particular, the invention relates to said compounds which are selective inhibitors of PDE10. The invention also relates to intermediates for preparation of said compounds; pharmaceutical compositions comprising said compounds; and the use of said compounds in a method for treating certain central nervous system (CNS) or other disorders.
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Page/Page column 36
(2008/06/13)
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- Fluorobenzamides and uses thereof
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The invention relates to fluorobenzamide derivatives of the formula wherein R1, R2, R3 R4, R5, R6 and R7 are as defined herein. =, The compounds of the invention are selective monoamine oxidase B inhibitors and therefore they are suitable for the treatment of diseases mediated by monoamine oxidase B, such as Alzheimer's disease or senile dementia.
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- FLUOROBENZAMIDES
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The present invention is concerned with fluorobenzamide derivatives of the general formula Wherein R1 is hydrogen, (C1-C6)-alkyl or hydroxy-(C1-C6)-alkyl; R2 is (C1-C6/su
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- Novel chiral fluoro-substituted benzoyloxybenzoates exhibiting an antiferroelectric mesophase
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The synthesis and properties of a new series of chiral fluoro-substituted benzoyloxybenzoates with nonchiral chains ranging from heptyloxy to octadecyloxy are reported. The mesomorphic properties of all of the compounds have been examined by a combination of optical polarized light microscopy, differential scanning calorimetry, and miscibility studies. They show rich polymorphism, and seven compounds exhibit the antiferroelectric (SmC*A) phase. The spontaneous polarization in the ferroelectric (SmC*) phase has been measured as a function of temperature for selected compounds.
- Shubashree,Sadashiva,Dhara, Surajit
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- The synthesis and mesomorphic properties of some novel antiferroelectric liquid crystals
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Several esters have been synthesised that exhibit the antiferroelectric smectic C phase. The core structures, like virtually all antiferroelectric materials, are very similar to that of MHPOBC. Lateral fluoro substituents have been used to reduce melting points and to investigate their effect on mesomorphic properties, spontaneous polarisation and tilt angle. A new device format reported by Lagerwall requires antiferroelectric liquid crystals with a 45° tilt angle. Novel antiferroelectric materials were prepared with fluoro substituents in lateral positions and in a terminal chain to provide low melting points, high antiferroelectric phase stability, high spontaneous polarisation and tilt angles of up to 45°. The synthetic routes to the novel materials are discussed, and the transition temperatures, tilt angles and spontaneous polarisations are compared to those of known materials.
- Hird, Michael,Goodby, John W.,Toyne, Kenneth J.,Gleeson, Helen F.,Peter Buxton,Seed, Alexander J.,Herbert, Mark R.
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p. 213 - 220
(2007/10/03)
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- Side-chain liquid crystal polymers derived from oxetane monomers containing 2- or 3-fluorophenyl moieties in the core of the mesogen
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Two series of side-chain liquid crystalline polymers were prepared by cationic ring-opening of oxetane substituted mesogens. Each of the terminally appended side chain polymers prepared had a flexible spacer length of six methylene units separating a meso
- Cowling,Toyne,Goodby
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p. 1590 - 1599
(2007/10/03)
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- Halogen-substituted phenyl benzyl ether derivatives
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A novel liquid crystal compound represented by the general formula (I): STR1 (wherein R is a straight or branched alkyl or alkoxy group having 1 to 20 carbon atoms, R* is an optically active alkyl group having 4 to 20 carbon atoms, X is a fluorine atom or a chlorine atom, and n is 1 or 2), a liquid crystal composition containing at least one liquid crystal compound of the general formula (I), a chiral smectic liquid crystal composition containing at least one liquid crystal compound of the general formula (I), and an optical switching element utilizing the chiral smectic liquid crystal composition containing at least one liquid crystal compound of the general formula (I) are described.
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