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Highly Potent (highly + potent)
Selected AbstractsDesign and Synthesis of Highly Potent and Plasma-Stable Dimeric Inhibitors of the PSD-95,NMDA Receptor Interaction,ANGEWANDTE CHEMIE, Issue 51 2009Anders Bach Dr. Im Doppel: Die Dimerisierung monomerer Peptidliganden für die PDZ-Domänen des Proteins PSD-95 (postsynaptische Dichte,95) liefert leistungsfähige Inhibitoren von Protein-Protein-Wechselwirkungen, die in Blutplasma stabil sind. Durch Optimierung der Länge des Polyethylenglycol-Linkers gelangt man zu Inhibitoren der PDZ1-2-Domäne (siehe Bild) mit bislang unerreichter Affinität. [source] Discovery of a Substituted 8-Arylquinoline Series of PDE4 Inhibitors: Structure,Activity Relationship, Optimization, and Identification of a Highly Potent, Well Tolerated, PDE4 Inhibitor.CHEMINFORM, Issue 9 2006Dwight Macdonald Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF. [source] 2-(2-Furanyl)-7-phenyl[1,2,4]triazolo[1,5-c]pyrimidin-5-amine Analogues: Highly Potent, Orally Active, Adenosine A2A Antagonists.CHEMINFORM, Issue 4 2006Part 1. Abstract For Abstract see ChemInform Abstract in Full Text. [source] Preparation of Non-Peptide, Highly Potent and Selective Antagonists of Arginine Vasopressin V1A Receptor by Introduction of Alkoxy Groups.CHEMINFORM, Issue 6 2004Yoshiaki Shimada Abstract For Abstract see ChemInform Abstract in Full Text. [source] Expression of c-ABL, c-KIT, and platelet-derived growth factor receptor-, in ovarian serous carcinoma and normal ovarian surface epitheliumCANCER, Issue 4 2003Rosemarie E. Schmandt Ph.D. Abstract BACKGROUND Tyrosine kinases, such as c-KIT, c-ABL, and platelet-derived growth factor-beta (PDGFR-,), are important regulators of cell growth. Highly potent and selective inhibitors of tyrosine kinases are being investigated as alternatives to standard chemotherapy. One such inhibitor, imatinib mesylate, is being used to treat gastrointestinal stromal tumors and chronic myelogenous leukemia. Ovarian carcinomas frequently develop resistance to conventional chemotherapeutic agents. Immunohistochemical expression of c-ABL, PDGFR-,, and c-KIT was evaluated in ovarian carcinomas to determine whether treatment with imatinib mesylate might be feasible. METHODS The expression of c-ABL, c-KIT, and PDGFR-, in tumors was evaluated by immunohistochemical analysis of 52 ovarian serous carcinomas, including 21 low-grade (well differentiated) and 31 high-grade (poorly differentiated) tumors. Fourteen normal ovaries were also evaluated. RESULTS In normal ovarian surface epithelium, c-ABL was expressed universally. PDGFR-, was expressed in the majority (93%) of samples of normal ovarian epithelium, whereas the c-KIT protein was undetectable in normal ovarian surface epithelium. Overall, c-ABL was expressed in 71% of serous carcinomas. c-ABL was expressed more frequently in the low-grade serous carcinomas (81%) compared with the high-grade serous carcinomas (65%). PDGFR-, expression was observed in 81% of serous carcinomas overall and was observed more frequently in higher-grade tumors. c-KIT immunohistochemical staining was absent in low-grade tumors but was present in 26% of high-grade serous carcinomas. CONCLUSIONS The majority of ovarian serous carcinomas express one or more of the kinases targeted by the tyrosine kinase inhibitor, imatinib mesylate, suggesting the potential usefulness of this drug in the treatment of ovarian carcinoma. Cancer 2003;98:758,64. © 2003 American Cancer Society. DOI 10.1002/cncr.11561 [source] Synthesis and deuterium labelling of the pure selective estrogen receptor modulator (SERM) acolbifene glucuronidesJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 3 2007Jean-Yves Sancéau Abstract Acolbifene (EM-652·HCl, SCH 57068·HCl), a highly potent and orally active selective estrogen receptor modulator (SERM), is at late stage clinical development for the treatment of estrogen-sensitive breast cancer. Acolbifene-7-glucuronide 1 (major) and acolbifene-4,-glucuronide 2 (minor) were identified as metabolites of acolbifene in the human. The two monoglucuronides and a diglucuronide 3 as well as the corresponding 2H-labelled derivatives 4,6 were synthesised for use as preclinical and clinical standards for LC,MS/MS analysis. All glucuronides were prepared by the Schmidt glycosylation of monoprotected acolbifene with a glucuronyl imidate at ,10°C to prevent epimerisation at the C-2 position. The two monoglucuronides 1 and 2 of acolbifene were separated by semi-preparative HPLC. Incorporation of three deuteriums was achieved by alkylation of chromanone 15 with C2H3MgI followed by dehydration with C2H3CO22H/2H2O. After chemical resolution and salt neutralisation, [2H3]acolbifene 19 was obtained with 99.4% enantiomeric purity and >98% isotopic purity. Copyright © 2007 John Wiley & Sons, Ltd. [source] Development of a potent and selective GPR7 (NPBW1) agonist: a systematic structure,activity study of neuropeptide BJOURNAL OF PEPTIDE SCIENCE, Issue 6 2007Maki Kanesaka Abstract Neuropeptide B (NPB) has been recently identified as an endogenous ligand for GPR7 (NPBW1) and GPR8 (NPBW2) and has been shown to possess a relatively high selectivity for GPR7. In order to identify useful experimental tools to address physiological roles of GPR7, we synthesized a series of NPB analogs based on modification of an unbrominated form of 23 amino acids with amidated C -terminal, Br(,)NPB-23-NH2. We confirmed that truncation of the N -terminal Trp residue resulted in almost complete loss of the binding affinity of NPB for GPR7 and GPR8, supporting the special importance of this residue for binding. Br(,)NPB-23-NH2 analogs in which each amino acid in positions 4, 5, 7, 8, 9, 10, 12 and 21 was replaced with alanine or glycine exhibited potent binding affinity comparable to the parent peptide. In contrast, replacement of Tyr11 with alanine reduced the binding affinity for both GPR7 and GPR8 four fold. Of particular interest, several NPB analogs in which the consecutive amino acids from Pro4 to Val13 were replaced with several units of 5-aminovaleric acid (Ava) linkers retained their potent affinity for GPR7. Furthermore, these Ava-substituted NPB analogs exhibited potent agonistic activities for GPR7 expressed in HEK293 cells. Among the Ava-substituted NPB analogs, analog 15 (Ava-5) and 17 (Ava-3) exhibited potency comparable to the parent peptide for GPR7 with significantly reduced activity for GPR8, resulting in high selectivity for GPR7. These highly potent and selective NPB analogs may be useful pharmacological tools to investigate the physiological and pharmacological roles of GPR7. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd. [source] Tolerance develops in spinal cord, but not in brain with chronic [Dmt1]DALDA treatmentBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2004Yong Ben Previously, we reported that H-2,,6,-dimethyltyrosine [Dmt1]- D -Arg-Phe-Lys-NH2 (DALDA), an analogue of the naturally occurring opioid peptide dermorphin, is a highly potent and selective mu receptor agonist with low cross-tolerance to morphine. In the present study, we investigated the effect of treating mice chronically with [Dmt1]DALDA. The AD50 of [Dmt1]DALDA (s.c.) increased eight-fold in animals given this drug chronically; in contrast, the AD50 increased two-fold in mice chronically treated with morphine. The AD50 of morphine (s.c.) in these [Dmt1]DALDA-treated animals was increased more than 120 times, while that of the more selective , agonist [D -Ala2 -MePhe4 -Gly-ol5]enkephalin (DAMGO) given intrathecally was increased more than 240 times. However, the AD50 of DAMGO given intracerebroventricularly was essentially the same in animals treated chronically with [Dmt1]DALDA as in naïve animals. The dose of naloxone required to precipitate withdrawal in [Dmt1]DALDA-treated animals was 20 times lower than that in morphine-tolerant animals. Using real-time quantitative PCR, we found that expression of the , opioid receptor, , opioid receptor, preproenkephalin and preprodynorphin genes was upregulated in the brain by [Dmt1]DALDA treatment. No significant changes in expression of opioid receptor or opioid peptide genes were detected in the spinal cord of [Dmt1]DALDA-treated mice, nor in the brain or spinal cord of morphine-treated mice. We conclude that a high degree of tolerance to [Dmt1]DALDA develops in the spinal cord but not brain, and cannot be accounted for by changes in expression of opioid receptors or opioid peptides in these tissues. British Journal of Pharmacology (2004) 143, 987,993. doi:10.1038/sj.bjp.0706007 [source] Dissection of Conformationally Restricted Inhibitors Binding to a ,-GlucosidaseCHEMBIOCHEM, Issue 5 2006Tracey M. Gloster Dr. Glycosidase inhibition, important in the quest for highly potent and specific drugs, can be achieved by mimicking the oxocarbenium ion-like transition-state species that form during the catalytic mechanism. Castanospermine (left) and calystegine B2 (right) are potent inhibitors that are conformationally restricted by the inclusion of ethylene linkers. Their binding to a ,-glucosidase from Thermotoga maritima has been studied by structural, kinetic and thermodynamic methods. Although both compounds inhibit with a similar potency, castanospermine derives the majority of it energetic contribution from enthalpy whereas calystegine B2 binding is more entropically driven. [source] Conformational analysis of endomorphin-1 by molecular dynamics methodsCHEMICAL BIOLOGY & DRUG DESIGN, Issue 4 2003B. Leitgeb Abstract: Endomorphin-1 (EM1, H-Tyr-Pro-Trp-Phe-NH2) is a highly potent and selective agonist for the ,-opioid receptor. A conformational analysis of this tetrapeptide was carried out by simulated annealing and molecular dynamics methods. EM1 was modeled in the neutral (NH2 -) and cationic (NH -) forms of the N-terminal amino group. The results of NMR measurements were utilized to perform simulations with restrained cis and trans Tyr1 -Pro2 peptide bonds. Preferred conformational regions in the ,2,,2, ,3,,3 and ,4,,4 Ramachandran plots were identified. The g(+), g(,) and trans rotamer populations of the side-chains of the Tyr1, Trp3 and Phe4 residues were determined in ,1 space. The distances between the N-terminal N atom and the other backbone N and O atoms, and the distances between the centers of the aromatic side-chain rings and the Pro2 ring were measured. The preferred secondary structures were determined as different types of , -turns and , -turns. In the conformers of trans -EM1, an inverse , -turn can be formed in the N-terminal region, but in the conformers of cis -EM1 the N-terminal inverse , -turn is absent. Regular and inverse , -turns were observed in the C-terminal region in both isomers. These , - and , -turns were stabilized by intramolecular H-bonds and bifurcated H-bonds. [source] 1-(1-Phenethylpiperidin-4-yl)-1-phenylethanols as Potent and Highly Selective 5-HT2A AntagonistsCHEMMEDCHEM, Issue 2 2006Timo Heinrich Dr. Abstract The discovery of a novel class of highly potent and selective 5-HT2Aantagonists is reported herein. Selectivity for the serotonin 5-HT2Areceptor was optimized, decreasing the affinity of these antagonists toward the adrenergic ,1 and dopaminergic D2 receptors, and especially to the 5-HT2Creceptor. A series of corresponding 7-substituted indoles is described for the first time as serotonergic ligands. The enantiomer R-(+)-1-(4-fluorophenyl)-1-{1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl} ethanol (R-(+)- 74) was identified to have superior affinity for the serotonergic 5-HT2Areceptor [IC50=0.37,nM] and selectivity toward the dopaminergic D2 - [IC50=2300,nM], adrenergic ,1 - [IC50=1000,nM] and 5-HT2Creceptors [IC50=490,nM]. [source] | |||||||||||||