- Bcl-2 INHIBITORS
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Disclosed herein is a compound of Formula (I) for inhibiting Bcl-2 and treating disease associated with undesirable bcl-2 activity (Bcl-2 related diseases), a method of using the compounds disclosed herein for treating dysregulated apoptotic diseases including cancers and treating autoimmune disease, and a pharmaceutical composition comprising the same.
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Paragraph 0347; 0348; 0349
(2019/11/19)
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- (2-benzylphenyl)piperazine derivatives and use thereof
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The invention discloses (2-benzylphenyl)piperazine derivatives, a use thereof, and a medicinal composition comprising above compounds. The derivatives and the medicinal composition are used for inhibiting serotonin reuptake. The invention also relates to
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Paragraph 0142; 0144; 0145; 0146; 0147
(2019/11/19)
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- Discovery of novel benzylidene-1,3-thiazolidine-2,4-diones as potent and selective inhibitors of the PIM-1, PIM-2, and PIM-3 protein kinases
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Novel substituted benzylidene-1,3-thiazolidine-2,4-diones (TZDs) have been identified as potent and highly selective inhibitors of the PIM kinases. The synthesis and SAR of these compounds are described, along with X-ray crystallographic, anti-proliferati
- Dakin, Les A.,Block, Michael H.,Chen, Huawei,Code, Erin,Dowling, James E.,Feng, Xiaomei,Ferguson, Andrew D.,Green, Isabelle,Hird, Alexander W.,Howard, Tina,Keeton, Erika K.,Lamb, Michelle L.,Lyne, Paul D.,Pollard, Hannah,Read, Jon,Wu, Allan J.,Zhang, Tao,Zheng, Xiaolan
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scheme or table
p. 4599 - 4604
(2012/08/07)
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- CHEMICAL COMPOUNDS 251
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The invention relates to chemical compounds of formula (I), and salts thereof. In some embodiments, the invention relates to inhibitors or modulators of PIM-1 and/or PIM-2, and/or PIM-3 protein kinase activity or enzyme function. In still further embodiments, the invention relates to pharmaceutical compositions comprising compounds disclosed herein, and their use in the prevention and treatment of PIM kinase related conditions and diseases, preferably cancer.
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Page/Page column 111
(2011/10/02)
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- Novel, versatile three-step synthesis of 1,2,3,4,10,10a-hexahydro- pyrazino[1,2- a ]indoles by intramolecular carbene-mediated C-H insertion
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A new convenient three-step synthesis of the privileged CNS scaffold 1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles has been developed. The method makes use of an intramolecular carbene-mediated C-H insertion in phenylpiperazine-derived tosyl-hydrazones m
- Krogsgaard-Larsen, Niels,Begtrup, Mikael,Herth, Matthias M.,Kehler, Jan
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experimental part
p. 4287 - 4299
(2011/02/22)
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- NOVEL CURCUMIN DERIVATIVE
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The present invention provides a novel compound that is structurally similar to curcumin and has a suppressive effect on Aβ aggregation, a degradative effect on Aβ aggregates, an inhibitory effect on β-secretase, and a protective effect on neurons. The novel compound is a compound represented by the following general formula (Ia) or a salt thereof: wherein R1 represents a 4-hydroxy-3-methoxyphenyl group or the like, and R2 represents a 1H-indol-6-yl group or the like.
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Page/Page column 101
(2009/12/07)
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- Structure-activity relationship studies on a series of piperazinebenzylalcohols and their ketone and amine analogs as melanocortin-4 receptor ligands
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A series of piperazinebenzylalcohols were prepared and studied to compare with their ketone and amine analogs as MC4R antagonists. Several benzylalcohols such as 14a and 14g displayed low nanomolar binding affinities (Ki 10 nM), and high sele
- Marinkovic, Dragan,Tucci, Fabio C.,Tran, Joe A.,Fleck, Beth A.,Wen, Jenny,Chen, Chen
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scheme or table
p. 4817 - 4822
(2009/05/26)
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- PHARMACOLOGICAL CHAPERONES FOR TREATING OBESITY
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The invention relates to methods of enhancing normal melanocortin-4 receptor (MC4R) activity, and to enhancing activity of an MC4R having a mutation which affects protein folding and/or processing of the MC4R. The invention provides a method of treating an individual having a condition in which increased activity of an MC4R at the cell surface would be beneficial, for example in obesity, by administering an effective amount of a pharmacological chaperone for the MC4R. The invention provides MC4R pharmacological chaperones which enhance the activity of MC4R. The invention further provides a method of screening to identify pharmacological chaperones which enhance folding of an MC4R in the endoplasmic reticulum (ER), in order to enhance the activity of the MC4R at the cell surface.
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Page/Page column 3/18
(2008/06/13)
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- Practical asymmetric synthesis of α-branched 2- piperazinylbenzylamines by 1,2-additions of organometallic reagents to N-tert-butanesulfinyl imines
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2-[4-(tert-Butoxycarbonyl)piperazinyl] benzylidene-tert-butanesulfinamides underwent nucleophilic 1,2-addition with different organometallic reagents to give highly diastereomerically enriched adducts. X-ray crystallography of the resulting α-branched N-B
- Jiang, Wanlong,Chen, Chen,Marinkovic, Dragan,Tran, Joe A.,Chen, Caroline W.,Arellano, L. Melissa,White, Nicole S.,Tucci, Fabio C.
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p. 8924 - 8931
(2007/10/03)
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- Structure-activity relationships of piperazinebenzylamines as potent and selective agonists of the human melanocortin-4 receptor
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SAR studies on a series of piperazinebenzenes directed toward the human melanocortin-4 receptor resulted in potent MC4R agonists. Replacement of the triazole moiety of an initial lead 4 by a basic nitrogen baring a lipophilic side-chain increased the binding affinities of these compounds. Analogs bearing an additional hetero-atom in the side-chain possessed good agonist potency. Thus, 11h had a Ki of 11 nM, and 13g exhibited an EC50 of 3.8 nM and a Ki of 6.4 nM.
- Pontillo, Joseph,Tran, Joseph A.,Arellano, Melissa,Fleck, Beth A.,Huntley, Rajesh,Marinkovic, Dragan,Lanier, Marion,Nelson, Jodie,Parker, Jessica,Saunders, John,Tucci, Fabio C.,Jiang, Wanlong,Chen, Caroline W.,White, Nicole S.,Foster, Alan C.,Chen, Chen
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p. 4417 - 4423
(2007/10/03)
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- 4-{(2R-[3-Aminopropionylamido]-3-(2,4-dichlorophenyl)propionyl} -1-{2-[(2-thienyl)ethylaminomethyl]phenyl}piperazine as a potent and selective melanocortin-4 receptor antagonist - Design, synthesis, and characterization
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Recent studies have demonstrated that melanocortin-4 receptor (MC4R) antagonists can prevent weight loss in tumor-bearing mice, which indicates clinical usage for the treatment of cachexia. In our efforts to develop potent and selective antagonists of the human MC4R, we designed piperazinebenzylamines bearing a 2,4-dichlorophenylalanine, by utilizing information derived from structure-activity relationships of MC4R agonists and mutagenesis results of the MC4R and peptide ligands. On the basis of known MC4R agonists such 6, we successfully synthesized potent MC4R antagonists exemplified by 10, which possesses a Ki value of 1.8 nM in binding affinity. 10 does not stimulate cAMP release in HEK 293 cells expressing the human MC4 receptor at 10 μM concentration. It was demonstrated by Schild analysis that 10 was a competitive functional antagonist with a pA2 value of 7.9 in the inhibition of α-MSH-stimulated cAMP accumulation. 10 also penetrated into the brain when dosed intravenously in rats.
- Chen, Chen,Pontillo, Joseph,Fleck, Beth A.,Gao, Yinghong,Wen, Jenny,Tran, Joe A.,Tucci, Fabio C.,Marinkovic, Dragan,Foster, Alan C.,Saunders, John
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p. 6821 - 6830
(2007/10/03)
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- Piperazinebenzylamines as potent and selective antagonists of the human melanocortin-4 receptor
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SAR studies of a series of piperazinebenzylamines resulted in the discovery of potent antagonists of the human melanocortin-4 receptor. Compounds 11c, 11d, and 11l, which had Ki values of 21, 14, and 15 nM, respectively, possessed low efficacy
- Pontillo, Joseph,Tran, Joseph A.,Fleck, Beth A.,Marinkovic, Dragan,Arellano, Melissa,Tucci, Fabio C.,Lanier, Marion,Nelson, Jodie,Parker, Jessica,Saunders, John,Murphy, Brian,Foster, Alan C.,Chen, Chen
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p. 5605 - 5609
(2007/10/03)
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- Synthesis and Structure-Activity Relationships of Novel Arylpiperazines as Potent and Selective Agonists of the Melanocortin Subtype-4 Receptor
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The melanocortin receptors have been implicated as potential targets for a number of important therapeutic indications, including inflammation, sexual dysfunction, and obesity. We identified compound 1, an arylpiperazine attached to the dipeptide H-D-Tic-D-p-Cl-Phe-OH, as a novel melanocortin subtype-4 receptor (MC4R) agonist through iterative directed screening of nonpeptidyl G-protein-coupled receptor biased libraries. Structure-activity relationship (SAR) studies demonstrated that substitutions at the ortho position of the aryl ring improved binding and functional potency. For example, the o-isopropyl-substituted compound 29 (Ki = 720 nM) possessed 9-fold better binding affinity compared to the unsubstituted aryl ring (Ki = 6600 nM). Sulfonamide 39 (Ki = 220 nM) fills this space with a polar substituent, resulting in a further 2-fold improvement in binding affinity. The most potent compounds such as the diethylamine 44 (Ki = 60 nM) contain a basic group at this position. Basic heterocycles such as the imidazole 50 (Ki = 110 nM) were similarly effective. We also demonstrated good oral bioavailability for sulfonamide 39.
- Richardson, Timothy I.,Ornstein, Paul L.,Briner, Karin,Fisher, Matthew J.,Backer, Ryan T.,Biggers, C. Kelly,Clay, Michael P.,Emmerson, Paul J.,Hertel, Larry W.,Hsiung, Hansen M.,Husain, Saba,Kahl, Steven D.,Lee, Jonathan A.,Lindstrom, Terry D.,Martinelli, Michael J.,Mayer, John P.,Mullaney, Jeffery T.,O'Brien, Thomas P.,Pawlak, Joseph M.,Revell, Kevin D.,Shah, Jikesh,Zgombick, John M.,Herr, R. Jason,Melekhov, Alex,Sampson, Peter B.,King, Chi-Hsin R.
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p. 744 - 755
(2007/10/03)
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- Aryl piperazine melanocortin MC4 receptor agonists
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Incorporation of substituted phenyl piperazine privileged structures into a known MC4 specific dipeptoid consensus sequence resulted in a series of potent (EC50=24 nM) and selective MC4-R agonists. We report the SAR of this series of compounds
- Dyck, Brian,Parker, Jessica,Phillips, Teresa,Carter, Lee,Murphy, Brian,Summers, Robin,Hermann, Julia,Baker, Tracy,Cismowski, Mary,Saunders, John,Goodfellow, Val
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p. 3793 - 3796
(2007/10/03)
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- Substituted piperazines and methods of use
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Selected substituted piperazine compounds are effective for prophylaxis and treatment of diseases, such as obesity and the like. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical com
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- Substituted aryl piperazines as neurokinin antagonists
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Disclosed are substituted aryl piperazines of Formula I STR1 are tachykinin receptor antagonists useful in the treatment of inflammatory diseases, pain or migraine, asthma and emesis. In particular compounds of Formula I are shown to be neurokinin antagonists.
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