- Discovery of a novel class of dimeric smac mimetics as potent IAP antagonists resulting in a clinical candidate for the treatment of cancer (AZD5582)
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A series of dimeric compounds based on the AVPI motif of Smac were designed and prepared as antagonists of the inhibitor of apoptosis proteins (IAPs). Optimization of cellular potency, physical properties, and pharmacokinetic parameters led to the identification of compound 14 (AZD5582), which binds potently to the BIR3 domains of cIAP1, cIAP2, and XIAP (IC50 = 15, 21, and 15 nM, respectively). This compound causes cIAP1 degradation and induces apoptosis in the MDA-MB-231 breast cancer cell line at subnanomolar concentrations in vitro. When administered intravenously to MDA-MB-231 xenograft-bearing mice, 14 results in cIAP1 degradation and caspase-3 cleavage within tumor cells and causes substantial tumor regressions following two weekly doses of 3.0 mg/kg. Antiproliferative effects are observed with 14 in only a small subset of the over 200 cancer cell lines examined, consistent with other published IAP inhibitors. As a result of its in vitro and in vivo profile, 14 was nominated as a candidate for clinical development.
- Hennessy, Edward J.,Adam, Ammar,Aquila, Brian M.,Castriotta, Lillian M.,Cook, Donald,Hattersley, Maureen,Hird, Alexander W.,Huntington, Christopher,Kamhi, Victor M.,Laing, Naomi M.,Li, Danyang,MacIntyre, Terry,Omer, Charles A.,Oza, Vibha,Patterson, Troy,Repik, Galina,Rooney, Michael T.,Saeh, Jamal C.,Sha, Li,Vasbinder, Melissa M.,Wang, Haiyun,Whitston, David
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p. 9897 - 9919
(2014/01/17)
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- USE OF 2-IMIDAZOLES FOR THE TREATMENT OF CNS DISORDERS
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The present invention relates to the use of compounds of formula (I) R1 is hydrogen, tritium, hydroxy, lower alkyl, lower alkoxy, halogen, nitro, amino or lower alkyl substituted by halogen; R2 is hydrogen, hydroxy or lower alkyl; X is N and Y is CH or CH2 or CH-lower alkyl or X is CH and Y is N; Q is CH2, O, NH, N-alkyl or N-SO2-alkyl or N-SO2-toluen-4-yl; W is CH2 or a bond are independently from one another 1, 2 or 3; when m is 2 or 3, R2 may m, n be the same or not; when n is 2 or 3, R1 may be the same or not; the dotted lines may each be independently from one another a bond or not; and to their pharmaceutically active salts, racemic mixtures, enantiomers, optical isomers and tautomeric forms of compounds of formula (I) for the preparation of medicaments for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder, stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.
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Page/Page column 64-65
(2010/11/28)
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- PGD2 RECEPTOR ANTAGONISTS FOR THE TREATMENT OF INFLAMMATORY DISEASES
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Disclosed are CRTH2 inhibitors represented by Structural Formula (I). The values for the variables of Structural Formula (I) are provided herein.
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Page/Page column 84
(2008/06/13)
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- Chromanylurea compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor and uses thereof
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Compounds that are antagonists of the VR1 receptor, having formula (I) [image] or a pharmaceutically acceptable salt, prodrug, or salt of a prodrug thereof, wherein A1, A2, A3, A4, R7, R8, R9, X, Y, Z, L, n, and m, are as defined herein, and are useful in disorders prevented or ameliorated by inhibiting the VR1 receptor.
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Page/Page column 21-22
(2008/06/13)
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- Reduction of Quinolinecarboxylic Acids by Raney Alloy
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The heterocyclic nucleus in quinolinecarboxylic acids is reduced by Raney alloy (nickel-aluminium) in alkaline media to give 1,2,3,4-tetrahydro-2-,3-,4-,5-,6-, and 8-quinolinecarboxylic acids and 8-methyl-5-quinolinecarboxylic acid and their ethyl esters.
- Gracheva, I. N.,Tochilkin, A. I.
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