112275-50-0Relevant articles and documents
Micelles for delivery of nitric oxide
Jo, Yun Suk,Van Der Vlies, Andrej,Gantz, Jay,Thacher, Tyler N.,Antonijevic, Sasa,Cavadini, Simone,Demurtas, Davide,Stergiopulos, Nikolaos,Hubbell, Jeffrey A.
, p. 14413 - 14418 (2009)
We designed block copolymer pro-amphiphiles and amphiphiles for providing very long-term release of nitric oxide (NO). A block copolymer of N-acryloylmorpholine (AM, as a hydrophile) and N-acryloyl-2,5-dimethylpiperazine (AZd, as a hydrophilic precursor) was synthesized. The poly(N-acryloyl-2,5- dimethylpiperazine) (PAZd) is water-soluble, but chemical reaction of the secondary amines with NO to form a N-diazeniumdiolate (NONOate) converts the hydrophilic PAZd into a hydrophobic poly(sodium-1-(N-acryloyl-2,5- dimethylpiperazin-1-yl)diazen-1-ium-1,2-diolate) (PAZd·NONOate), driving aggregation. The PAM block guides this process toward micellization, rather than precipitation, yielding ca. 50 nm spherical micelles. The hydrophobic core of the micelle shielded the NONOate from the presence of water, and thus protons, which are required for NO liberation, delaying release to a remarkable 7 d half-life. Release of the NO returned the original soluble polymer. The very small NO-loaded micelles were able to penetrate complex tissue structures, such as the arterial media, opening up a number of tissue targets to NO-based therapy.
Discovery of G Protein-Biased Antagonists against 5-HT7R
Kwag, Rina,Lee, Jieon,Kim, Doyoung,Lee, Haeun,Yeom, Miyoung,Woo, Jiwan,Cho, Yakdol,Kim, Hak Joong,Kim, Jeongjin,Keum, Gyochang,Jeon, Byungsun,Choo, Hyunah
, p. 13766 - 13779 (2021/10/01)
5-HT7R belongs to a family of G protein-coupled receptors and is associated with a variety of physiological processes in the central nervous system via the activation of the neurotransmitter serotonin (5-HT). To develop selective and biased 5-HT7R ligands, we designed and synthesized a series of pyrazolyl-diazepanes 2 and pyrazolyl-piperazines 3 , which were evaluated for binding affinities to 5-HTR subtypes and functional selectivity for G protein and β-arrestin signaling pathways of 5-HT7R. Among them, 1-(3-(3-chlorophenyl)-1H-pyrazol-4-yl)-1,4-diazepane 2c showed the best binding affinity for 5-HT7R and selectivity over other 5-HTR subtypes. It was also revealed as a G protein-biased antagonist. The self-grooming behavior test was performed with 2c in vivo with Shank3-/-transgenic (TG) mice, wherein 2c significantly reduced self-grooming duration time to the level of wild-type mice. The results suggest that 5-HT7R could be a potential therapeutic target for treating autism spectrum disorder stereotypy.
Optimization of 5-substituted thiazolyl ureas and 6-substituted imidazopyridines as potential HIV-1 latency reversing agents
Blackmore, Timothy R.,Jacobson, Jonathan,Jarman, Kate E.,Lewin, Sharon R.,Nguyen, William,Purcell, Damian F.,Sabroux, Helene Jousset,Sleebs, Brad E.
, (2020/04/08)
A persistent latent reservoir of virus in CD4+ T cells is a major barrier to cure HIV. Activating viral transcription in latently infected cells using small molecules is one strategy being explored to eliminate latency. We previously described the use of a FlpIn.FM HEK293 cellular assay to identify and then optimize the 2-acylaminothiazole class to exhibit modest activation of HIV gene expression. Here, we implement two strategies to further improve the activation of viral gene expression and physicochemical properties of this class. Firstly, we explored rigidification of the central oxy-carbon linker with a variety of saturated heterocycles, and secondly, investigated bioisosteric replacement of the 2-acylaminothiazole moiety. The optimization process afforded lead compounds (74 and 91) from the 2-piperazinyl thiazolyl urea and the imidazopyridine class. The lead compounds from each class demonstrate potent activation of HIV gene expression in the FlpIn.FM HEK293 cellular assay (both with LTR EC50s of 80 nM) and in the Jurkat Latency 10.6 cell model (LTR EC50 220 and 320 nM respectively), but consequently activate gene expression non-specifically in the FlpIn.FM HEK293 cellular assay (CMV EC50 70 and 270 nM respectively) manifesting in cellular cytotoxicity. The lead compounds have potential for further development as novel latency reversing agents.
UR-DEBa176: A 2,4-Diaminopyrimidine-Type Radioligand Enabling Binding Studies at the Human, Mouse, and Rat Histamine H4 Receptors
Bartole, Edith,Littmann, Timo,Tanaka, Miho,Ozawa, Takeaki,Buschauer, Armin,Bernhardt, Günther
supporting information, p. 8338 - 8356 (2019/10/11)
Differences in sequence homology between human (h), mouse (m), and rat (r) histamine H4 receptors (H4R) cause discrepancies regarding affinities, potencies, and/or efficacies of ligands and therefore compromise translational animal models and the applicability of radioligands. Aiming at a radioligand enabling robust and comparative binding studies at the h/m/rH4Rs, 2,4-diaminopyrimidines were synthesized and pharmacologically investigated. The most notable compounds identified were two (partial) agonists with comparable potencies at the h/m/rH4Rs: UR-DEBa148 (N-neopentyl-4-(1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)pyrimidin-2-amine bis(2,2,2-trifluoroacetate), 43), the most potent [pEC50 (reporter gene assay) = 9.9/9.6/10.3] compound in the series being slightly G-protein biased and UR-DEBa176 [(R)-4-[3-(dimethylamino)pyrrolidin-1-yl]-N-neopentylpyrimidin-2-amine bis(2,2,2-trifluoroacetate), 46, pEC50 (reporter gene assay) = 8.7/9.0/9.2], a potential "cold" form of a tritiated H4R ligand. After radiolabeling, binding studies with [3H]UR-DEBa176 ([3H]46) at the h/m/rH4Rs revealed comparable Kd values (41/17/22 nM), low nonspecific binding (11-17%, aKd), and fast associations/dissociations (25-30 min) and disclosed [3H]UR-DEBa176 as useful molecular tool to determine h/m/rH4R binding affinities for H4R ligands.
Diamines compound single-Boc protection method
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Paragraph 0020; 0044; 0046, (2017/08/31)
The invention relates to a diamines compound single-Boc protection method. The method includes following steps: enabling t-butylazidoformate and the diamines compound to react in an organic solvent at 0-30 DEG C to obtain a single-Boc-protected diamines compound. T-butylazidoformate is used as a Boc protection reagent, so that reaction selectivity can be improved effectively; a byproduct is nitrogen which escapes directly from a reaction system. By the method, the defect that a byproduct-isobutene is generated when Boc anhydride is taken as a raw material is overcome, and the problems of thick reaction system and difficulty in purification are solved thoroughly. The method is high in reaction efficiency, simple in aftertreatment and suitable for industrial production.
ACTIVATORS OF HIV LATENCY
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Page/Page column 71; 72, (2018/04/19)
The present invention relates to novel compounds which active HIV expression in latently infected cells. More particularly, the invention relates to pharmaceutical compositions comprising the novel compounds and their use in activating HIV expression in latently infected cells. Further still, the invention relates to pharmaceutical compositions comprising the novel compounds in combination with anti-HIV therapy compounds and their use in treating HIV infection in both animals and humans. The invention further provides means for preparing the compounds.
FUSED RING HETEROARYL COMPOUNDS AND THEIR USE AS TRK INHIBITORS
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Paragraph 0592; 0593, (2016/07/05)
The disclosure provides novel chemical compounds represented by Formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. The compounds can be used as an inhibitor of Trk and are useful in the treatment of pain, cancer, inflammation, neurodegenerative disease and certain infectious diseases. In some compounds of Formula I, Q is —CH═CR3C(O)NR4R5, —C≡CC(O)NR4R5, or
NOVEL 1,4-DIAZEPAM PDE-5 INHIBITOR DERIVATIVES
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Paragraph 0110; 0111, (2013/04/23)
It describes a compound of general formula I, methods for its preparation, pharmaceutical compositions containing it and the use of the latter in the treatment of erectile dysfunction.
Evaluation of N-phenyl homopiperazine analogs as potential dopamine D 3 receptor selective ligands
Li, Aixiao,Mishra, Yogesh,Malik, Maninder,Wang, Qi,Li, Shihong,Taylor, Michelle,Reichert, David E.,Luedtke, Robert R.,MacH, Robert H.
, p. 2988 - 2998 (2013/07/05)
A series of N-(2-methoxyphenyl)homopiperazine analogs was prepared and their affinities for dopamine D2, D3, and D4 receptors were measured using competitive radioligand binding assays. Several ligands exhibited high binding affinity and selectivity for the D3 dopamine receptor compared to the D2 receptor subtype. Compounds 11a, 11b, 11c, 11f, 11j and 11k had Ki values ranging from 0.7 to 3.9 nM for the D3 receptor with 30- to 170-fold selectivity for the D 3 versus D2 receptor. Calculated log P values (log P = 2.6-3.6) are within the desired range for passive transport across the blood-brain barrier. When the binding and the intrinsic efficacy of these phenylhomopiperazines was compared to those of previously published phenylpiperazine analogues, it was found that (a) affinity at D2 and D3 dopamine receptors generally decreased, (b) the D3 receptor binding selectivity (D2:D3 Ki value ratio) decreased and, (c) the intrinsic efficacy, measured using a forskolin-dependent adenylyl cyclase inhibition assay, generally increased.
Exploration of ring size in a series of cyclic vicinal diamines with σ1 receptor affinity
Moussa, Iman A.,Banister, Samuel D.,Manoli, Miral,Doddareddy, Munikumar Reddy,Cui, Jinquan,MacH, Robert H.,Kassiou, Michael
supporting information; experimental part, p. 5493 - 5497 (2012/09/22)
Imidazolidine and 1,4-diazepane analogs of N-(2-benzofuranyl)methyl- N′-(4-alkoxybenzyl)piperazines were prepared to explore the effect of ring contraction and expansion on σ receptor affinity and subtype selectivity within a series of cyclic diamines. In vitro receptor binding assays revealed that all cyclic vicinal diamines possessed affinity and selectivity for σ1 receptors. The imidazolidines possessed nanomolar σ1 affinities (Ki = 6.45-53.5 nM), and relatively low levels of subtype selectivity (σ2/σ1 = 58-237). However, the piperazines and diazepanes achieved picomolar σ1 interactions, with Ki ranges of 0.05-10.28 and 0.10-0.194 nM, respectively. Moreover, the piperazines and diazepanes showed excellent discrimination over the σ2 receptor, with σ1 selectivities of 143-16140 and 220-11542, respectively.
