- 2-Phenyl-4-piperazinylbenzimidazoles: Orally active inhibitors of the gonadotropin releasing hormone (GnRH) receptor
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Antagonism of the gonadotropin releasing hormone (GnRH) receptor has shown positive clinical results in numerous reproductive tissue disorders such as endometriosis, prostate cancer and others. Traditional therapy has been limited to peptide agonists and
- Pelletier, Jeffrey C.,Chengalvala, Murty,Cottom, Josh,Feingold, Irene,Garrick, Lloyd,Green, Daniel,Hauze, Diane,Huselton, Christine,Jetter, James,Kao, Wenling,Kopf, Gregory S.,Lundquist IV, Joseph T.,Mann, Charles,Mehlmann, John,Rogers, John,Shanno, Linda,Wrobel, Jay
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p. 6617 - 6640
(2008/12/22)
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- 3-BENZOIMIDAZOLYL-PYRAZOLOPYRIDINES USEFUL IN TREATING KINASE DISORDERS
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The present invention is directed to novel 3-benzoimidazolyl-pyrazolopyridine compounds of formula (I): and pharmaceutically acceptable forms thereof and their synthesis and use as inhibitors of serine-threonine protein kinases and tyrosine protein kinases and interactions thereof.
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Page/Page column 83
(2008/06/13)
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- High-affinity α-aminobutyric acid A/benzodiazepine ligands: Synthesis and structure - Activity relationship studies of a new series of tetracyclic imidazoquinoxalines
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A series of tetracyclic imidazoquinoxaline analogs was developed which constrain the carbonyl group of the partial agonist 3-(5-cyclopropyl-1,2,4- oxadiazol-3-yl)-5-[(dimethylamino)carbonyl]4,5-dihydroimidazo[1,5- a]quinoxaline (2, U-91571) away from the benzene ring. These analogs orient the carbonyl group in the opposite direction of the previously reported full agonist 1-(5-cyclopropyl- 1,2,4-oxadiazol-3-yl)- 12,12a-dihydroimidazo[1,5- a]pyrrolo[2,1-c]quinoxalin- 10(11H)one (3, U-89267). A number of approaches were utilized to form the 'bottom' ring of this tetracyclic ring system including intramolecular cyclizations promoted by Lewis acids or base, as well as metal-carbenoid conditions. The size and substitution pattern of the additional ring was widely varied. Analogs within this series had high affinity for the benzodiazepine receptor on the α-aminobutyric acid A chloride ion channel complex. From TBPS shift and Cl- current assays, the in vitro efficacy of compounds within this class ranged from antagonists to partial agonists with only 18a identified as a full agonist. Additionally, several analogs were quite potent at antagonizing metrazole-induced seizures indicating possible anticonvulsant or anxiolytic activity. Unlike 3, analogs in this series did not have high affinity for the diazepam insensitive α6β2δ2 subtype. These results suggest that either constraining the carbonyl group away from the benzene ring or the greater planarity that results from the additional cyclic structure provides analogs with partial agonist properties and prevents effective interaction with the α6β2δ2 subtype.
- Mickelson, John W.,Jacobsen, E. Jon,Carter, Donald B.,Im, Haesook K.,Im, Wha Bin,Schreur, Peggy J. K. D.,Sethy, Vimala H.,Tang, Andy H.,McGee, James E.,Petke, James D.
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p. 4654 - 4666
(2007/10/03)
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- Imidazo[1,5-A]quinoxalines
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An invention relating to Imidazo[1,5-a]quinoxalines (I) STR1 which do not contain an endocyclic carbonyl group and which are useful as anxiolytic and sedative/hypnotic agents.
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