Modulation of SETDB1 activity by APQ ameliorates heterochromatin condensation, motor function, and neuropathology in a Huntington's disease mouse model.

The present study describes evaluation of epigenetic regulation by a small molecule as the therapeutic potential for treatment of Huntington's disease (HD). We identified 5-allyloxy-2-(pyrrolidin-1-yl)quinoline (APQ) as a novel SETDB1/ESET inhibitor using a combined in silico and in vitro cell based screening system. APQ reduced SETDB1 activity and H3K9me3 levels in a HD cell line model. In particular, not only APQ reduced H3K9me3 levels in the striatum but it also improved motor function and neuropathological symptoms such as neuronal size and activity in HD transgenic (YAC128) mice with minimal toxicity. Using H3K9me3-ChIP and genome-wide sequencing, we also confirmed that APQ modulates H3K9me3-landscaped epigenomes in YAC128 mice. These data provide that APQ, a novel small molecule SETDB1 inhibitor, coordinates H3K9me-dependent heterochromatin remodelling and can be an epigenetic drug for treating HD, leading with hope in clinical trials of HD.

Identification of Optically Active Pyrimidine Derivatives as Selective 5-HT2C Modulators.

A series of pyrimidine derivatives 4a-i were synthesized and evaluated for their binding affinities towards 5-HT2C receptors. With regard to designed molecules 4a-i, the influence of the size of alkyl ether and the absolute configuration of a stereogenic center on the 5-HT2C binding affinity and selectivity was studied. The most promising diasteromeric mixtures 4d and 4e were selected in the initial radioligand binding assay and they were further synthesized as optically active forms starting from optically active alcohols 5d and 5e, prepared by an enzymatic kinetic resolution. Pyrimidine analogue (R,R)-4e displayed an excellent 5-HT2C binding affinity with good selectivity values against a broad range of other 5-HT receptor subtypes.

Synthesis and biological evaluation of picolinamides and thiazole-2-carboxamides as mGluR5 (metabotropic glutamate receptor 5) antagonists.

We described here the synthesis and biological evaluation of picolinamides and thiazole-2-carboxamides as potential mGluR5 antagonists. We found that a series of thiazole derivatives 6 showed better inhibitory activity against mGluR5. Compounds 6bc and 6bj have been identified as potent antagonists (IC50=274 and 159nM) showing excellent in vitro stability profile. Molecular docking study using the crystal structure of mGluR5 revealed that our compounds 6bc and 6bj fit the allosteric binding site of mavoglurant well.

Synthesis and biological evaluation of aryl isoxazole derivatives as metabotropic glutamate receptor 1 antagonists: a potential treatment for neuropathic pain.

Glutamate is the major excitatory neurotransmitter and known to activate the metabotropic and ionotropic glutamate receptors in the brain. Among these glutamate receptors, metabotropic glutamate receptor 1 (mGluR1) has been implicated in various brain disorders including anxiety, schizophrenia and chronic pain. Several studies demonstrated that the blockade of mGluR1 signaling reduced pain responses in animal models, suggesting that mGluR1 is a promising target for the treatment of neuropathic pain. In this study, we have developed mGluR1 antagonists with an aryl isoxazole scaffold, and identify several compounds that are orally active in vivo. We believe that these compounds can serve as a useful tool for the investigation of the role of mGluR1 and a promising lead for the potential treatment of neuropathic pain.

Facile diverted synthesis of pyrrolidinyl triazoles using organotrifluoroborate: discovery of potential mPTP blockers.

This article describes the rapid and diversified synthesis of pyrrolidinyl triazoles for the discovery of mitochondrial permeability transition pore (mPTP) blockers. The 1,3-dipolar cycloaddition of ethynyl trifluoroborate with azidopyrrolidine produced a key intermediate, triazolyl trifluoroborate 4, which subsequently underwent a Suzuki-Miyaura coupling reaction to afford a series of 1,4-disubstituted triazoles 2. Subsequent biological evaluation of these derivatives indicated 2ag and 2aj as the most potent mPTP blockers exhibiting excellent cytochrome P450 (CYP) stability when compared to the previously reported oxime analogue 1. The present work clearly demonstrates that a 1,2,3-triazole can be used as a stable oxime surrogate. Furthermore, it suggests that late-stage diversification through coupling reactions of organotrifluoroborates is suitable for the rapid discovery of biologically active molecules.

Efficient synthesis of mibefradil analogues: an insight into in vitro stability.

This article describes the synthesis and biological evaluation of a chemical library of mibefradil analogues to investigate the effect of structural modification on in vitro stability. The construction of the dihydrobenzopyran structure in mibefradil derivatives 2 was achieved through two efficient approaches based on a diastereoselective intermolecular Reformatsky reaction and an intramolecular carbonyl-ene cyclization. In particular, the second strategy through the intramolecular carbonyl-ene reaction led to the formation of a key intermediate 3 in a short and highly stereoselective way, which has allowed for practical and convenient preparation of analogues 2. Using this protocol, we could obtain 22 new mibefradil analogues 2, which were biologically tested for in vitro efficacies against T-type calcium channels and metabolic stabilities. Among the synthesized compounds, we found that analogue 2aa containing a dihydrobenzopyran ring and a secondary amine linker showed high % remaining activities of the tested CYP enzymes retaining the excellent T-type calcium channel blocking activity. These findings indicated that the structural modification of 1 was effective for improving in vitro stability, i.e., reducing CYP inhibition and metabolic degradation.

Synthesis and biological evaluation of 2-substituted quinoline 6-carboxamides as potential mGluR1 antagonists for the treatment of neuropathic pain.

A series of 2-amino and 2-methoxy quinoline-6-carboxamide derivatives have been synthesized and their metabotropic glutamate receptor type 1 (mGluR1) antagonistic activities were evaluated in a functional cell-based assay. The compound 13c showed the highest potency with IC50 value of 2.16 µM against mGluR1. Finally, in vivo evaluation of 13c in the rat spinal nerve ligation (SNL) model exhibited weak analgesic effects with regard to both mechanical allodynia and cold allodynia.

Crystal structure of (E)-N-[(E)-3-(4-meth-oxy-phen-yl)allyl-idene]naphthalen-1-amine.

In the title compound, C20H17NO, the dihedral angle between the mean planes of the 4-meth-oxy-phenyl ring and the naphthalene ring is 69.50 (7)°. The meth-oxy group is almost coplanar with the benzene ring to which it is connected [Cb-Cb-Om-Cm torsion angle of -7.9 (2)°; b = benzene and m = meth-oxy] and the imine group displays a C-C-N=C torsion angle is -57.2 (2)°. The imine (C=N) group has an E conformation. In the crystal, weak π-π inter-actions between the benzene rings [centroid-centroid distance = 3.7781 (10) Å] are observed.

Synthesis and biological evaluation of 2-(arylethynyl)quinoline derivatives as mGluR5 antagonists for the treatment of neuropathic pain.

We described here the synthesis and biological evaluation of mGluR5 antagonists containing a quinoline ring structure. Using intracellular calcium mobilization assay (FDSS assay), we identified compound 5n, showing high inhibitory activity against mGluR5. In addition, it was found that compound 5n has excellent stability profile. Finally, this compound exhibited favorable analgesic effects in spinal nerve ligation model of neuropathic pain, which is comparable to gabapentin.

(E)-2,2'-[3-(4-Chloro-phen-yl)prop-2-ene-1,1-di-yl]bis-(3-hy-droxy-5,5-di-methyl-cyclo-hex-2-en-1-one).

The title compound, C25H29ClO4, adopts a trans conformation about the C=C double bond and the di-methyl-cyclo-hexenone rings both show an envelope conformation with the dimethyl-substituted C atom as the flap. In the mol-ecule, the hy-droxy and carbonyl groups form two intra-molecular O-H⋯O hydrogen bonds typical for xanthene derivatives. In the crystal, weak C-H⋯O hydrogen bonds link the mol-ecules into chains running parallel to the a-axis direction.

(E)-N-(3,3-Di-phenyl-allyl-idene)naph-thal-en-1-amine.

The title compound, C25H19N, adopts an E conformation about the C=N bond. The naphthalene ring system and the phenyl rings form dihedral angles 38.1 (1), 46.9 (8) and 48.5 (1)°, respectively, with the mean plane of the central enimino fragment. The crystal packing exhibits no directional close contacts.

9-[(E)-2-(4-Chloro-phen-yl)ethen-yl]-3,3,6,6-tetra-methyl-2,3,4,5,6,7,8,9-octa-hydro-1H-xanthene-1,8-dione.

In the title compound, C25H27ClO3, each of the cyclo-hexenone rings adopts an envelope conformation, whereas the six-membered pyran ring adopts a flattened boat conformation, with the O and methine C atoms deviating from the plane of the other four atoms. The C=C double bond is in the trans conformation. In the crystal, weak C-H⋯O hydrogen bonds link the mol-ecules into chains running parallel to the b axis.

(E)-N-(3,3-Di-phenyl-allyl-idene)-2-(tri-fluoro-meth-yl)aniline.

In the title compound, C22H16F3N, the C=N bond of the central imine group adopts an E conformation. The dihedral angles between the 2-(tri-fluoro-meth-yl)phenyl ring and the benzene rings are 9.34 (1) and 68.8 (1)°. The imine group displays a C-C-N=C torsion angle of 41.6 (3)°. In the crystal, weak C-H⋯F hydrogen bonds link the mol-ecules into chains parallel to the b-axis direction.

(E)-2,2'-[3-(4-Fluoro-phen-yl)prop-2-ene-1,1-di-yl]bis-(3-hy-droxy-5,5-dimethyl-cyclo-hex-2-en-1-one).

In the title compound, C25H29FO4, each cyclo-hexenone ring has an envelope conformation with the dimethyl-substituted atom as the flap. The hy-droxy and carbonyl groups form two intra-molecular O-H⋯O hydrogen bonds, as is typical for xanthene derivatives. In the crystal, very weak C-H⋯O hydrogen bonds link mol-ecules into dimers.

(E)-9-(4-Fluoro-styr-yl)-3,3,6,6-tetra-methyl-3,4,5,6,7,9-hexa-hydro-2H-xanthene-1,8-dione.

In the title compound, C25H27FO3, each of the cyclo-hexenone rings adopts a half-chair conformation, whereas the six-membered pyran ring adopts a flattened boat conformation, with the O and methine C atoms deviating by 0.0769 (15) and 0.196 (2) Å, respectively, from the plane of the other four atoms (r.m.s. deviation = 0.004 Å). The C=C double bond adopts an E conformation. The dihedral angle between the benzene and pyran (all atoms) rings is 89.94 (10)°. In the crystal, weak C-H⋯O hydrogen bonds link the mol-ecules into chains running parallel to the b axis.

(E)-N-[(E)-3-(4-Nitro-phen-yl)allyl-idene]naphthalen-1-amine.

In the title compound, C19H14N2O2, the dihedral angle between the mean planes of the 4-nitro-phenyl ring and the naphthalene ring system is 12.79 (2)°. The imine group displays a C-C-N=C torsion angle of 41.0 (2)° and the C=N group has an E conformation. In the crystal, weak C-H⋯O hydrogen bonds link molecules into layers parallel to the b axis.

5-HT2c receptor selectivity and structure-activity relationship of N-methyl-N-(1-methylpiperidin-4-yl)benzenesulfonamide analogs.

Agonists of the 5-HT(2C) receptor have attracted much attention as therapeutic agents for the treatment of obesity. Subtype selectivity against other 5-HT(2) receptors is one of the most important prerequisites for reducing side effects. We present the synthesis of N-methyl-N-(1-methylpiperidin-4-yl)benzenesulfonamide analogs and their structure-activity relationship studies on 5-HT(2A) and 5-HT(2C) receptors. Although the compounds showed nanomolar activity to the 5-HT(2C) receptor, their selectivity against the 5-HT(2A) receptor was modest to low. Molecular modeling studies using homology modeling and docking simulation revealed that selectivity originated from subtype specific residues. The observed binding modes and receptor-ligand interactions provided us a clue for optimizing the selectivity against the 5-HT(2A) receptor.

(E)-2,2'-[3-(2-Nitro-phen-yl)prop-2-ene-1,1-di-yl]bis-(3-hy-droxy-cyclo-hex-2-en-1-one).

In the title compound, C(21)H(21)NO(6), each of the cyclo-hexenone rings adopts a half-chair conformation. Each of the pairs of hy-droxy and carbonyl O atoms are oriented to allow for the formation of intra-molecular O-H⋯O hydrogen bonds, which are typical of xanthene derivatives.

[2-(4-Chloro-phen-yl)-5-phenyl-oxolan-3-yl](cyclo-penten-yl)methanone.

In the title compound, C(22)H(21)ClO(2), the oxolane ring adopts a twisted conformation. The dihedral angles between the mean plane of the oxolane ring and the mean planes of the 4-chloro-phenyl, phenyl and cyclo-pentenyl rings are 71.81 (18), 76.9 (18) and 82.08 (18)°, respectively.

9-[(E)-2-(2-Meth-oxy-phen-yl)ethen-yl]-3,4,5,6,7,9-hexa-hydro-2H-xanthene-1,8-dione.

In the title compound, C(22)H(22)O(4), the two cyclo-hexenone rings adopt half-chair conformations, whereas the six-membered pyran ring adopts a flattened boat conformation, with the O and methine C atoms deviating from the plane of the other four atoms by 0.142 (2) and 0.287 (2)Å, respectively. In the crystal, weak C-H⋯O hydrogen bonds link mol-ecules into chains running parallel to the a axis.