83598-55-4Relevant articles and documents
The identification of indacaterol as an ultralong-acting inhaled β2-adrenoceptor agonist
Baur, Fran?ois,Beattie, David,Beer, David,Bentley, David,Bradley, Michelle,Bruce, Ian,Charlton, Steven J.,Cuenoud, Bernard,Ernst, Roland,Fairhurst, Robin A.,Faller, Bernard,Farr, David,Keller, Thomas,Fozard, John R.,Fullerton, Joe,Garman, Sheila,Hatto, Julia,Hayden, Claire,He, Handan,Howes, Colin,Janus, Diana,Jiang, Zhengjin,Lewis, Christine,Loeuillet-Ritzler, Frederique,Moser, Heinz,Reilly, John,Steward, Alan,Sykes, David,Tedaldi, Lauren,Trifilieff, Alexandre,Tweed, Morris,Watson, Simon,Wissler, Elke,Wyss, Daniel
supporting information; experimental part, p. 3675 - 3684 (2010/07/16)
Following a lipophilicity-based hypothesis, an 8-hydroxyquinolinone 2-aminoindan derived series of β2-adrenoceptor agonists have been prepared and evaluated for their potential as inhaled ultralong-acting bronchodilators. Determination of their activities at the human β2-adrenoceptor receptor showed symmetrical substitution of the 2-aminoindan moiety at the 5- and 6-positions delivered the targeted intermediate potency and intrinsic-efficacy profiles relative to a series of clinical reference β2-adrenoceptor agonists. Further assessment with an in vitro superfused electrically stimulated guinea-pig tracheal-strip assay established the onset and duration of action time courses, which could be rationalized by considering the lipophilicity, potency, and intrinsic efficacy of the compounds. From these studies the 5,6-diethylindan analogue indacaterol 1c was shown to possess a unique profile of combining a rapid onset of action with a long duration of action. Further in vivo profiling of 1c supported the long duration of action and a wide therapeutic index following administration to the lung, which led to the compound being selected as a development candidate.
Dopamine D3 receptor antagonists. 1. Synthesis and structure-activity relationships of 5,6-Dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans
Haadsma-Svensson,Cleek,Dinh,Duncan,Haber,Huff,Lajiness,Nichols,Smith,Svensson,Zaya,Carlsson,Lin
, p. 4716 - 4732 (2007/10/03)
5,6-Dimethoxy-2-(N-dipropyl)-aminoindan (3, PNU-99194A) was found to be a selective dopamine D3 receptor antagonist with potential antipsychotic properties in animal models. To investigate the effects of nitrogen substitution on structure- activity relationships, a series of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans were synthesized and evaluated in vitro for binding affinity and metabolic stability. The results indicate that substitution at the amine nitrogen of the 2-aminoindans is fairly limited to the di-N-propyl group in order to achieve selective D3 antagonists. Thus, combinations of various alkyl groups were generally inactive at the D3 receptor. Although substitution with an N-alkylaryl or N-alkylheteroaryl group yields compounds with potent D3 binding affinity, the D2 affinity is also enhanced, resulting in a less than 4-fold preference for the D3 receptor site, and no improvements in metabolic stability were noted. A large-scale synthesis of the D3 antagonist 3 has been developed that has proven to be reproducible with few purification steps. The improvements include the use of 3,4-dimethoxybenzaldehyde as a low-cost starting material to provide the desired 5,6-dimethoxy-1-indanone 5c in good overall yield (65%) and the formation of a soluble silyl oxime 17 that was reduced efficiently with BH3·Me2S. The resulting amino alcohol was alkylated and then deoxygenated using a Lewis acid and Et3SiH to give the desired product 3 in good overall yield of (～65%) from the indanone 5c.
AMINOCYCLOALKANOBENZODIOXOLES AS BETA-3 SELECTIVE ADRENERGIC AGENTS
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, (2008/06/13)
The invention is antiobesity/antidiabetic/beta-3 agonists of the formula STR1 wherein the substituents R o, R 1, R 4, R. sub.4 ', R 5, R 6 or n are as defined in the specification.
