- Discovery of novel α1-adrenoceptor ligands based on the antipsychotic sertindole suitable for labeling as PET ligands
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The synthesis and in vitro preclinical profile of a series of 5-heteroaryl substituted analogs of the antipsychotic drug sertindole are presented. Compounds 1-(4-fluorophenyl)-3-(1-methylpiperidin-4-yl)-5-(pyrimidin-5-yl)-1H- indole (Lu AA27122, 3i) and 1-(4-fluorophenyl)-5-(1-methyl-1H-1,2,4-triazol-3- yl)-3-(1-methylpiperidin-4-yl)-1H-indole (3l) were identified as high affinity α1A-adrenoceptor ligands with Ki values of 0.52 and 0.16 nM, respectively, and with a >100-fold selectivity versus dopamine D2 receptors. Compound 3i showed almost equal affinity for α1B- (Ki = 1.9 nM) and α1D- adrenoceptors (Ki = 2.5 nM) as for α1A, as well as moderate affinity for 5-HT1B (Ki = 13 nM) and 5-HT 6 (Ki = 16 nM) receptors, whereas 3l showed >40-fold selectivity toward all other targets tested. Based on in vitro assays for assessment of permeability rates and extent, it is predicted that both compounds enter the brain of rats, non-human primates, as well as humans, and as such are good candidates to be carried forward for further evaluation as positron emission tomography (PET) ligands.
- Jorgensen, Morten,Jorgensen, Pernille N.,Christoffersen, Claus T.,Jensen, Klaus G.,Balle, Thomas,Bang-Andersen, Benny
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p. 196 - 204
(2013/02/22)
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- PYRAZOLO[3,4-D]PYRIMIDINE COMPOUNDS AND THEIR USE AS PDE2 INHIBITORS AND/OR CYP3A4 INHIBITORS
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The present invention provides, inter alia, compounds of Formula (I) and pharmaceutically acceptable salts thereof, to processes for the preparation of, intermediates used in the preparation of, and compositions containing such compounds and the uses of such compounds as a method for the treatment of a disease or condition selected from the group consisting of central nervous system disorders, cognitive disorders, schizophrenia, dementia and other disorders in a mammal. The present invention further provides compounds of Formula (Id) and pharmaceutically acceptable salts thereof as CYP3A4 selective inhibitors.
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Page/Page column 44-45
(2013/02/27)
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- Discovery of 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl]-3-(2, 4-difluorophenyl)urea (Nelotanserin) and Related 5-Hydroxytryptamine 2A Inverse Agonists for the Treatment of Insomnia
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Insomnia affects a growing portion of the adult population in the U.S. Most current therapeutic approaches to insomnia primarily address sleep onset latency. Through the 5-hydroxytryptamine2A (5-HT2A) receptor, serotonin (5-HT) plays a role in the regulation of sleep architecture, and antagonists/ inverse-agonists of 5-HT2A have been shown to enhance slow wave sleep (SWS). We describe here a series of 5-HT2A inverse-agonists that when dosed in rats, both consolidate the stages of NREM sleep, resulting in fewer awakenings, and increase a physiological measure of sleep intensity. These studies resulted in the discovery of 1-[3-(4-bromo-2- methyl-2i/-pyrazol-3-yl)-4-methoxyphenyl]-3-(2,4-difluorophenyl)urea (Nelotanserin), a potent inverse-agonist of 5-HT2A that was advanced into clinical trials for the treatment of insomnia.
- Teegarden, Bradley R.,Li, Hongmei,Jayakumar, Honnappa,Strah-Pleynet, Sonja,Dosa, Peter I.,Selaya, Susan D.,Kato, Naomi,Elwell, Katie H.,Davidson, Jarrod,Cheng, Karen,Saldana, Hazel,Frazer, John M.,Whelan, Kevin,Foster, Jonathan,Espitia, Stephan,Webb, Robert R.,Beeley, Nigel R. A.,Thomsen, William,Morairty, Stephen R.,Kilduff, Thomas S.,Al-Shamma, Hussien A.
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experimental part
p. 1923 - 1936
(2010/08/05)
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- Niacin Receptor Agonists, Compositions Containing Such Compounds and Methods of Treatment
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The present invention encompasses compounds of Formula I: as well as pharmaceutically acceptable salts and hydrates thereof, that are useful for treating atherosclerosis, dyslipidemias and the like. Pharmaceutical compositions and methods of use are also included.
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Page/Page column 54
(2009/04/24)
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- CRF RECEPTOR ANTAGONISTS AND METHODS RELATING THERETO
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CRF receptor antagonists are disclosed which have utility in the treatment of a variety of disorders, including the treatment of disorders manifesting hypersecretion of CRF in a warm-blooded animals, such as stroke. The CRF receptor antagonists of this invention have the following structure (I), including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, Y, Ar, and Het are as defined herein. Compositions containing a CRF receptor antagonist in combination with a pharmaceutically acceptable carrier are also disclosed, as well as methods for use of the same.
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Page/Page column 74
(2010/02/12)
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- DIARYL AND ARYLHETEROARYL UREA DERIVATIVES AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR USEFUL FOR THE PROPHYLAXIS AND TREATMENT OF DISORDERS RELATED THERTO
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The present invention relates to certain pyrazole derivatives of Formula (I) and pharmaceutical compositions thereof that modulate the activity of the 5-HT2A serotonin receptor. Compounds and pharmaceutical compositions thereof are directed to
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Page/Page column 101
(2010/02/10)
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- Synthesis of pinacol esters of 1-alkyl-1H-pyrazol-5-yl- and 1-alkyl-1H-pyrazol-4-ylboronic acids
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Starting from 1H-pyrazol, a wide number of 1-alkyl-1H-pyrazol-4-yl and 1-alkyl-1H-pyrazol-5-ylboronic acids and their pinacol esters were synthesized and characterized. The key step in the described methodology is the regioselective lithiation of the pyrazole ring. The synthesized pinacolates are stable under prolonged storage and can be used as convenient reagents in organic synthesis.
- Ivachtchenko, Alexandre V.,Kravchenko, Dmitry V.,Zheludeva, Valentina I.,Pershin, Dmitry G.
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p. 931 - 939
(2007/10/03)
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- DIARYLAMINE AND ARYLHETEROARYLAMINE PYRAZOLE DERIVATIVES AS MODULATORS OF 5HT2A
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One aspect of the present invention relates to certain diarylamine and arylheteroarylamine pyrazole derivatives of Formula (A) and pharmaceutical compositions that modulate the activity of the human 5HT2A serotonin receptor. Compounds and pharmaceutical c
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