- The identification of indacaterol as an ultralong-acting inhaled β2-adrenoceptor agonist
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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.
- 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
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supporting information; experimental part
p. 3675 - 3684
(2010/07/16)
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- Beta2-adrenoceptor agonists
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Compounds of formula in free or salt or solvate form, where Ar is a group of formula Y is carbon or nitrogen and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, n, p, q and r are as defined in the specification, their preparation and their use as pharmaceuticals, particularly for the treatment of obstructive or inflammatory airways diseases.
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Page/Page column 14
(2008/06/13)
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- Dopamine D3 receptor antagonists. 1. Synthesis and structure-activity relationships of 5,6-Dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans
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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.
- Haadsma-Svensson,Cleek,Dinh,Duncan,Haber,Huff,Lajiness,Nichols,Smith,Svensson,Zaya,Carlsson,Lin
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p. 4716 - 4732
(2007/10/03)
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- alpha -amino acid amides, preparation thereof and the therapeutical use thereof
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PCT No. PCT/EP97/03773 Sec. 371 Date Feb. 19, 1999 Sec. 102(e) Date Feb. 19, 1999 PCT Filed Jul. 15, 1997 PCT Pub. No. WO98/03472 PCT Pub. Date Jan. 29, 1998The present invention relates to serinamide, glycinamide, alaninamide and phenylalaninamide deriva
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- AMINOCYCLOALKANOBENZODIOXOLES AS BETA-3 SELECTIVE ADRENERGIC AGENTS
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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.
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- Conformationally Restricted Congeners of Dopamine Derived from 2-Aminoindan
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Two series of N-substituted 2-aminoindan systems have been prepared: 4,5-dihydroxy-2-aminoindan (1) has a hydroxylation pattern analogous to the α-conformer of dopamine, and 5,6-dihydroxy-2-aminoindan (2) has a hydroxylation pattern of the β conformer of dopamine.All members of both series demonstrated only extremely weak binding to calf caudate homogenate.Certain N-alkylated 4,5-dihydroxyindans were violent emetics in the dog and were potent in blockade of the effect of stimulation of the cardioaccelerator nerve of the cat.In contrast, the 5,6-dihydroxy series displayed low or no activity/potency in these assays.Conformational analysis of the 2-aminoindan system is described and discussed.
- Cannon, Joseph G.,Perez, Julio A.,Bhatnagar, Rambir K.,Long, John Paul,Sharabi, Fouad M.
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p. 1442 - 1446
(2007/10/02)
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- A study of the conformational requirements for direct adrenergic stimulation
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A group of tetrahydroisoquinoline derivatives was prepared as fixed cisoid and 2 indanamines as fixed transoid analogs of the adrenergic neurotransmitter, norepinephrine. The compounds were evaluated in comparison with their closest, flexible counterparts, epinine and (R) and (S) α methyldopamine, respectively, for direct α and β adrenergic activities in vivo and in vitro. Results obtained in vivo on the cat nictitating membrane indicate that a transoid conformation is better than cisoid for inducing direct α stimulation but that a cisoid conformation does not preclude direct α activity. No conclusion could be reached with regard to conformational requirements for direct β activity.
- Gray,Reit,Ackerly,Hava
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p. 1023 - 1027
(2007/10/04)
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