- Micelles for delivery of nitric oxide
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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.
- Jo, Yun Suk,Van Der Vlies, Andrej,Gantz, Jay,Thacher, Tyler N.,Antonijevic, Sasa,Cavadini, Simone,Demurtas, Davide,Stergiopulos, Nikolaos,Hubbell, Jeffrey A.
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Read Online
- Discovery of G Protein-Biased Antagonists against 5-HT7R
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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.
- 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
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p. 13766 - 13779
(2021/10/01)
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- Optimization of 5-substituted thiazolyl ureas and 6-substituted imidazopyridines as potential HIV-1 latency reversing agents
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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.
- Blackmore, Timothy R.,Jacobson, Jonathan,Jarman, Kate E.,Lewin, Sharon R.,Nguyen, William,Purcell, Damian F.,Sabroux, Helene Jousset,Sleebs, Brad E.
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- UR-DEBa176: A 2,4-Diaminopyrimidine-Type Radioligand Enabling Binding Studies at the Human, Mouse, and Rat Histamine H4 Receptors
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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.
- Bartole, Edith,Littmann, Timo,Tanaka, Miho,Ozawa, Takeaki,Buschauer, Armin,Bernhardt, Günther
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supporting information
p. 8338 - 8356
(2019/10/11)
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- Diamines compound single-Boc protection method
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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.
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Paragraph 0020; 0044; 0046
(2017/08/31)
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- ACTIVATORS OF HIV LATENCY
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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.
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Page/Page column 71; 72
(2018/04/19)
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- FUSED RING HETEROARYL COMPOUNDS AND THEIR USE AS TRK INHIBITORS
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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
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Paragraph 0592; 0593
(2016/07/05)
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- NOVEL 1,4-DIAZEPAM PDE-5 INHIBITOR DERIVATIVES
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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.
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Paragraph 0110; 0111
(2013/04/23)
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- Evaluation of N-phenyl homopiperazine analogs as potential dopamine D 3 receptor selective ligands
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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.
- Li, Aixiao,Mishra, Yogesh,Malik, Maninder,Wang, Qi,Li, Shihong,Taylor, Michelle,Reichert, David E.,Luedtke, Robert R.,MacH, Robert H.
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p. 2988 - 2998
(2013/07/05)
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- Exploration of ring size in a series of cyclic vicinal diamines with σ1 receptor affinity
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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.
- Moussa, Iman A.,Banister, Samuel D.,Manoli, Miral,Doddareddy, Munikumar Reddy,Cui, Jinquan,MacH, Robert H.,Kassiou, Michael
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supporting information; experimental part
p. 5493 - 5497
(2012/09/22)
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- Evaluation of quinazoline analogues as glucocerebrosidase inhibitors with chaperone activity
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Gaucher disease is a lysosomal storage disorder (LSD) caused by deficiency in the enzyme glucocerebrosidase (GC). Small molecule chaperones of protein folding and translocation have been proposed as a promising therapeutic approach to this LSD. Most small molecule chaperones described in the literature contain an iminosugar scaffold. Here we present the discovery and evaluation of a new series of GC inhibitors with a quinazoline core. We demonstrate that this series can improve the translocation of GC to the lysosome in patient-derived cells. To optimize this chemical series, systematic synthetic modifications were performed and the SAR was evaluated and compared using three different readouts of compound activity: enzymatic inhibition, enzyme thermostabilization, and lysosomal translocation of GC.
- Marugan, Juan J.,Zheng, Wei,Motabar, Omid,Southall, Noel,Goldin, Ehud,Westbroek, Wendy,Stubblefield, Barbara K.,Sidransky, Ellen,Aungst, Ronald A.,Lea, Wendy A.,Simeonov, Anton,Leister, William,Austin, Christopher P.
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experimental part
p. 1033 - 1058
(2011/04/25)
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- Synthesis and anti-hepatitis C virus activity of novel ethyl 1H-indole-3-carboxylates in vitro
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A series of ethyl 1H-indole-3-carboxylates 9a1- 6 and 9b1-2 were prepared and evaluated in Huh-7.5 cells. Most of the compounds exhibited anti-hepatitis C virus (HCV) activities at low concentration. The selectivity indices of inhibition on entry and replication of compounds 9a2 (>10; >16.7) and 9b1 (>6.25; >16.7) were higher than those of the other evaluated compounds, including the lead compound Arbidol (ARB, 6; 15). Moreover, the selective index of inhibition on entry of compound 9a3 (>6.25) was higher than that of ARB (6). Of these three initial hits, compound 9a2 was the most potent.
- Sellitto, Grazia,Faruolo, Aurora,De Caprariis, Paolo,Altamura, Sergio,Paonessa, Giacomo,Ciliberto, Gennaro
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experimental part
p. 6143 - 6148
(2010/09/15)
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- Identification of a butyrophenone analog as a potential atypical antipsychotic agent: 4-[4-(4-Chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one
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The synthesis and exploration of novel butyrophenones have led to the identification of a diazepane analogue of haloperidol, 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one (compound 13) with an interesting multireceptor binding profile. Compound 13 was evaluated for its binding affinities at DA subtype receptors, 5HT subtype receptors, H-1, M-1 receptors and at NET, DAT, and SERT transporters. At each of these receptors, compound 13 was equipotent or better than several of the standards currently in use. In in vivo mouse and rat models to evaluate its efficacy and propensity to elicit catalepsy and hence EPS in humans, compound 13 showed similar efficacy as clozapine and did not produce catalepsy at five times its ED50 value.
- Ablordeppey, Seth Y.,Altundas, Ramazan,Bricker, Barbara,Zhu, Xue Y.,Suresh Kumar, Eyunni V.K.,Jackson, Tanise,Khan, Abdul,Roth, Bryan L.
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p. 7291 - 7301
(2008/12/23)
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- Mono-acylation of piperazine and homopiperazine via ionic immobilization
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A method for the selective mono-acylation of piperazine and homopiperazine has been developed. In a flow system, initially the diamine is ionically immobilized on a sulfonic acid funtionalized silica gel, acylated with an appropriate reagent and finally liberated with ammonic methanol. Examples with high yield and purity are presented.
- Pringle, Wallace
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p. 5047 - 5049
(2008/12/21)
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- FUSED BICYCLIC AROMATIC COMPOUNDS THAT ARE USEFUL IN TREATING SEXUAL DYSFUNCTION
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The present invention relates to the use of compounds of formula (I) for the treatment of sexual dysfunction and to compositions containing compounds of formula (I) for the treatment of sexual dysfunction.
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- Il-8 receptor anatagonists
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This invention relates to novel compounds of Formula (I), and compositions thereof, useful in the treatment of disease states mediated by the chemokine, Interleukin-8 (IL-8).
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- PIPERAZINE AND HOMOPIPERAZINE COMPOUNDS
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Compounds are provided having a piperazine or homopiperazine ring which are useful in the treatment of thrombosis.
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- Beta lactam compounds and their use as inhibitors of tryptase
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Compounds of the formulas: are disclosed. These compounds inhibit tryptase as well as other enzyme systems or are selective tryptase inhibitors and are useful as antiinflammatory agents particularly in the treatment of chronic asthma.
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Page column 92
(2010/11/29)
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- Azetidinylpropylpiperidine derivatives, intermediates and use as tachykinin antagonists
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Compounds of the formula (I): where X1, A, Ar1, X and R are as defined in the specification, and pharmaceutically-acceptable salts thereof, are new, and are useful as tachykinin inhibitors which act at the NK1, NK2and NK3receptors or a combination of two or more thereof.
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- DIARYLALKYL CYCLIC DIAMINE DERIVATIVES AS CHEMOKINE RECEPTOR ANTAGONISTS
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Cyclic diamines of formula (I) or their pharmacologically acceptable acid addition salts, and their medical applications are described. These compounds inhibit the action of chemokines such as MIP-la and/or MCP-l on target cells, and are useful as a therapeutic drug and/or preventative drug in diseases, such as atherosclerosis, rheumatoid arthritis, and the like where blood monocytes and lymphocytes infiltrate into tissues.
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- Piperazine and homopiperazine derivatives, pharmaceutical compositions containing them and process for preparing same
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This invention relates to novel compounds of the general formula (I) and the pharmaceutically acceptable acid addition salts thereof. In the general formula (I) STR1 wherein Lip, A1, A2, Het and n are defined as in the specification. The compounds of the general formula (I) inhibit the lipid peroxidation and therefore, they are useful for the treatment or prevention of diseases and conditions wherein the inhibition of lipid peroxidation is desirable.
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- Piperazine and homopiperazine derivatives, pharmaceutical compositions containing them and process for preparing the same
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The lipid peroxidation inhibiting piperazine and homopiperazine derivatives of the general formula (I) and the pharmaceutically acceptable acid addition salts thereof, Lip stands for hydrogen; C15 20 alkyl; C10 20 alkanoyl or C10 20 alkenoyl; trityl optionally substituted by halogen; adamantyl; 1- or 2-naphthyloxy or oxo-substituted tetrahydronaphthyloxy; or an amine protective group commonly used e.g. in the peptide chemistry;, A1 and A2 are selected independently from the group consisting of a single bond and C2 3 alkylene optionally substituted by hydroxy or oxo;, n is 1 or 2; and, Het represents, a group of the general formula (a), wherein, R1 is amino or 1-pyrrolidinyl;, or a 4-chloro-3-oxo-2,3-dihydro-5-pyridazinyl group of the formula (b); or a 4-amino-6,7-dimethoxy-2-quinazolinyl group of the formula (c); or a 4,7-diamino-6-phenyl-2-pteridinyl group of the formula (d); or a 2,7-diamino-6-phenyl-4-pteridinyl group of the formula (e); or a 2,4,7-triamino-6-pteridinylcarbonyl group of the formula (f); or a group of the general formula (g); wherein, X means oxygen, sulfur or nitrogen optionally substituted by lower alkyl,with the frist proviso that, when Het stands for a group of the general fromula (a) and both A1 and A2 mean single bonds then Lip may not be hydrogen;, with the second priviso that, when Lip is different from naphthyloxy or oxo-substituted tetrahydronaphthyloxy then A1 means a single bond;, with the third proviso that, when Lip represents naphthyloxy or oxo-substituted tetrahydronaphthyloxy then A1 may not be a single bond, as well as with the fourth proviso that, A1 and A2 cannot simultaneously stand for C2 3 alkylene optionally substituted by hydroxy or oxo.
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