- Affinity-Based Selectivity Profiling of an In-Class Selective Competitive Inhibitor of Acyl Protein Thioesterase 2
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Activity-based protein profiling (ABPP) has revolutionized the discovery and optimization of active-site ligands across distinct enzyme families, providing a robust platform for in-class selectivity profiling. Nonetheless, this approach is less straightfo
- Won, Sang Joon,Eschweiler, Joseph D.,Majmudar, Jaimeen D.,Chong, Fei San,Hwang, Sin Ye,Ruotolo, Brandon T.,Martin, Brent R.
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supporting information
p. 215 - 220
(2017/03/08)
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- Identification of novel GLUT inhibitors
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The compound class of 1H-pyrazolo[3,4-d]pyrimidines was identified using HTS as very potent inhibitors of facilitated glucose transporter 1 (GLUT1). Extensive structure–activity relationship studies (SAR) of each ring system of the molecular framework was established revealing essential structural motives (i.e., ortho-methoxy substituted benzene, piperazine and pyrimidine). The selectivity against GLUT2 was excellent and initial in vitro and in vivo pharmacokinetic (PK) studies are encouraging.
- Siebeneicher, Holger,Bauser, Marcus,Buchmann, Bernd,Heisler, Iring,Müller, Thomas,Neuhaus, Roland,Rehwinkel, Hartmut,Telser, Joachim,Zorn, Ludwig
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p. 1732 - 1737
(2016/07/27)
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- 5HT1A ANTAGONIST USEFUL FOR IN VIVO IMAGING
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The present invention provides a novel compound of formula (I) useful for in vivo imaging of 5-HT1 A receptors in a subject. Also provided by the present invention is a precursor compound useful in the preparation of the compound of the inventi
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Page/Page column 26; 27
(2013/03/26)
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- NOVEL SYNTHESIS METHOD
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The present invention relates to a method of making compounds having affinity for the 1 A subtype of the serotonin receptor, i.e. 5HT1A. The method of the present invention provides advantages over the known methods of synthesis. The compounds
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Page/Page column 22
(2013/04/10)
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- Discovery of 3-aryl-5-acylpiperazinyl-pyrazoles as antagonists to the NK3 receptor
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A series of 3-aryl-5-acylpiperazinyl-pyrazoles (e.g., 3a-b) initially identified through a high-throughput screening campaign using the aequorin Ca2+ bioluminescence assay as novel, potent small molecule antagonists of the G protein-coupled hum
- Hoveyda, Hamid R.,Roy, Marie-Odile,Blanc, Sebastien,No?l, Sophie,Salvino, Joseph M.,Ator, Mark A.,Fraser, Graeme
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p. 1991 - 1996
(2011/04/24)
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- Compositions, Synthesis, And Methods Of Using Piperazine Based Antipsychotic Agents
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The present invention provides novel piperazine derivatives which can be advantageously used for treating schizophrenia and related psychoses such as acute manic, bipolar disorder, autistic disorder and depression.
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Page/Page column 18; 25
(2009/12/23)
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- Synthesis of novel WAY 100635 derivatives containing a norbornene group and radiofluorination of [18F]AH1.MZ as a serotonin 5-HT1A receptor antagonist for molecular imaging
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5-HT1A receptors are involved in a variety of psychiatric disorders and in vivo molecular imaging of the 5-HT1A status represents an important approach to analyze and treat these disorders. We report herein the synthesis of three new
- Herth, Matthias M.,Kramer, Vasko,Roesch, Frank
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experimental part
p. 201 - 207
(2010/06/14)
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- COMPSITIONS, SYNTHESIS, AND METHODS OF USING QUINOLINE BASED ATYPICAL ANTIPSYCHOTIC AGENTS
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The present invention provides novel quinolinone derivatives which can be advantageously used for treating schizophrenia and related psychoses such as acute manic, bipolar disorder, autistic disorder, and depression.
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Page/Page column 25
(2009/01/20)
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- 1,2-Di(cyclic)substituted benzene compounds
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In one aspect, the present invention provides compounds having formula (1) or (100), a salt thereof or a hydrate of the foregoing, which compounds exhibit excellent cell adhesion inhibitory action or cell infiltration inhibitory action, and are useful as therapeutic or prophylactic agents for various inflammatory diseases and autoimmune diseases associated with adhesion and infiltration of leukocytes, such as inflammatory bowel disease (particularly ulcerative colitis or Crohn's disease), irritable bowel syndrome; rheumatoid arthritis, psoriasis, multiple sclerosis, asthma and atopic dermatitis. wherein R10 represents optionally substituted cycloalkyl, etc., R20-23 represent hydrogen, alkyl, alkoxy, etc., R30-32 represent hydrogen, alkyl, oxo, etc., and R40 represents optionally substituted alkyl, etc.
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Page/Page column 61-62
(2008/06/13)
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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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- A novel class of nonpeptidic biaryl inhibitors of human cathepsin K
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A novel series of nonpeptidic biaryl compounds was identified as potent and reversible inhibitors of cathepsin K. The P2-P3 amide bond of a known amino acetonitrile dipeptide 1 was replaced with a phenyl ring, thereby giving rise to this biaryl series that retained potency vs cathepsin K and showed an improved selectivity profile against other cathepsins. Structural modification within this series resulted in the identification of compound (R)-2, a potent human cathepsin K inhibitor (IC50 = 3 nM) that is selective versus cathepsins B (IC50 = 3950 nM), L (IC50 = 3725 nM), and S (IC50 = 2010 nM). In an in vitro assay involving rabbit osteoclasts and bovine bone, compound (R)-2 inhibited bone resorption with an IC 50 of 95 nM. It was shown that, unlike some peptidic nitrile inhibitors of cysteine proteases, the nitrile moiety of (R)-2 is not converted to the corresponding amide 3 by cathepsin K. This indicates that this class of nonpeptidic nitrile inhibitors is unlikely to be hydrolyzed by cysteine proteases. Furthermore, the inhibition of cathepsin K by compound (R)-2 was shown to be fully reversible and not observably time-dependent. To demonstrate the efficacy of compound (R)-2 in vivo, it was administered to ovariectomized (OVX) rhesus monkeys at 20 mg/kg, po once daily for 8 days, and a urinary marker of bone turnover, N-telopeptide of type I collagen (uNTx), was measured. During the eight-day dosing period, the mean reduction by compound (R)-2 in uNTx was 80% (p 0.001). This demonstrates that inhibition of cathepsin K leads to an inhibition of this bone resorption marker in OVX rhesus monkeys and strongly suggests that inhibition of cathepsin K is a viable therapeutic approach for the treatment of osteoporosis.
- Robichaud, Jo?l,Oballa, Renata,Prasit, Peppi,Falgueyret, Jean-Pierre,Percival, M. David,Wesolowski, Gregg,Rodan, Sevgi B.,Kimmel, Donald,Johnson, Colena,Bryant, Cliff,Venkatraman, Shankar,Setti, Eduardo,Mendonca, Rohan,Palmer, James T.
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p. 3709 - 3727
(2007/10/03)
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- Certain aryl-aliphatic and heteroaryl-aliphatic piperazinyl pyrazines and their use in the treatment of serotonin-related diseases
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Compounds of the general formula (I): wherein the variables are as defined in the specification are useful for the prophylaxis or treatment of serotonin-related, especially 5-HT2receptor-related, diseases in human beings or animals, particularly diseases related to the 5-HT2creceptor, especially diseases such as eating disorders, memory disorders, schizophrenia, mood disorders, anxiety disorders, pain, sexual dysfunctionions, and urinary disorders.
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