b-Adrenergic blocking agents. Nitrogen heteroaryl-substituted 2-propanolamines and ethanolamines

Meyer, Robert; Stratton, Charlotte D.; Hastings, S.; Corey, Ruth M.

doi:10.1021/jm00268a010

Cited by 17 publications

(4 citation statements)

References 4 publications

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“…All other solvents were used as provided without further purification. The preparation of compounds 3 , 8a , and 8f have been reported. , Compounds 11a , 11b , 11c , 11d , 11e , 11j , and 11k 38 were synthesized as previously described. N , N -Diethylethylenediamine, 11f , N , N -diisopropylethylenediamine, 11g , 1-(2-aminoethyl)pyrrolidine, 11h , and 1-(2-aminoethyl)piperidine, 11i, were commercially available from Aldrich.…”

Section: Methodsmentioning

confidence: 99%

“…The synthetic methodology reported previously for the synthesis of 3 was applicable to the new compounds described herein. Dialkylaminoethylamines 11a − e , 1-(2-aminoethyl)-4-methylipiperidine, 11j , and the 1-(2-aminoethyl)-4-benzylpiperazine, 11k , were not commercially available and were synthesized as described previously, − (Scheme ). Alkylation of dialkylamines or a nitrogen heterocycle 9a − e , 9j, and 9k with chloroacetonitrile or bromoacetonitrile provided intermediates 10a − e , 10j , and 10k , which were reduced to the corresponding dialkylaminoethylamines.…”

Section: Chemistrymentioning

confidence: 99%

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5-(2-Aminoethyl)dibenzo[c,h][1,6]naphthyridin-6-ones: Variation of N-Alkyl Substituents Modulates Sensitivity to Efflux Transporters Associated with Multidrug Resistance

et al. 2005

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5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxydibenzo[c,h][1,6]naphthyridin-6-one (ARC-111) has potent TOP1-targeting activity and pronounced antitumor activity. Several analogues of ARC-111 were synthesized with NH2, N-alkyl, N,N-dialkyl, pyrrolidinyl, piperidinyl, and piperazinyl substituents at the 2-position of the 5-ethyl group. The relative TOP1-targeting activity and cytotoxicity of these structural analogues were assessed in RPMI8402 and P388 tumor cells and their camptothecin-resistant variants CPT-K5 and P388/CPT45, respectively. Potent TOP1-targeting activity was retained within a series of mono N-alkyl analogues that included NHCH2CH3, NHCH(CH3)2, and NHC(CH3)3. TOP1-targeting activity was diminished by the presence of a N-benzyl moiety. In a comparison of a series of N-alkyl-N-isopropyl analogues, activity decreased in the order CH3 > CH2CH3 > CH(CH3)2. Cytotoxicity in RPMI8402 and P388 did correlate with TOP1-targeting activity. Cytotoxic activity was also determined in KB3-1 cells and its variants KB/V-1 and KBH5.0. As KB/V-1 cells overexpress MDR1 and KBH5.0 cells overexpress BCRP, decreased cytotoxicity in these cell lines relative to the parent cell line is indicative of compounds that are substrates for these efflux transporters. In view of their diminished cytotoxicity in KB/V-1 cells, it appears that the likely demethylated metabolites of ARC-111, i.e., where NH2 or NHCH3 replaces the N(CH3)2 at the 2-position of the 5-ethyl substituent, are substrates for MDR1. In contrast, no significant difference in cytotoxicity among these three cell lines was observed with other N-alkyl analogues, including NHC2H5, NHCH(CH3)2, NHC(CH3)3, N(CH3)2, N(CH2CH3)2, NCH3(CH(CH3)2), and either the pyrrolidinyl or the piperidinyl analogues. The 2-(piperazinyl) analogues were associated with diminished cytotoxicity in KB/V-1 cells, suggesting that the second basic amino substituent is associated with their recognition as substrates by MDR1. Comparative studies on the antitumor activity of ARC-111 and its N-demethylated derivatives (the NHCH3 and NH2 analogues) against SJ-BT45 medulloblastoma xenografts in scid mice revealed that the secondary amine metabolite is at least as active as ARC-111 in vivo, although the primary amine derivative was significantly less potent.

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Section: Methodsmentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

5-(2-Aminoethyl)dibenzo[c,h][1,6]naphthyridin-6-ones: Variation of N-Alkyl Substituents Modulates Sensitivity to Efflux Transporters Associated with Multidrug Resistance

et al. 2005

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“…A further set of polycyclic agents demonstrated by Meyer et ul. (4) to have varying P-blocking activities was investigated for their effects on R F PFC (Table 1). All agents were tested at lo-' and M .…”

Section: Phenanth-eth (T-but-meth) Phenanth-prop (T-but) I-propranolomentioning

confidence: 99%

Drugs affecting the release of rheumatoid factor in a plaque‐forming cell assay

Moore

Robbins

Rose

et al. 1978

Arthritis & Rheumatism

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Addition of propranolol to the agarose phase of a plaque-forming cell (PFC) assay for rheumatoid factor (RF) caused reduction in the number of plaques seen. This reduction in rheumatoid factor plaque-forming cell ( R F PFC) did not depend upon an effect at the 8-adrenergic receptor, since d-and I-propranolol reduced equally well. Furthermore, in a series of polycyclic compounds with varying &receptor blocking capabilities there was no agreement between plaque reduction and blocking. When propranolol was tested in the agarose in an anti-sheep erythrocyte (SRC) plaque assay (anti-SRC PFC), it had no inhibitory effect, but it was capable of inhibiting the generation of new anti-SRC PFC in an in vitro culture. Propranolol is thought to exert these effects through its membrane stabilizing (anesthetic) properties. E. ROSE, and JOHN H. VAUGHANThe production and release of rheumatoid factor (RF) by lymphoid cells of certain patients with rheumatoid arthritis (RA) have been shown in bone marrows, synovial fluids, and peripheral bloods by a hemolytic plaque-forming cell ( R F PFC) assay (1). The target cells used were sheep cells sensitized with reduced and alkylated rabbit IgG antibody, which lysed directly in the presence of added rheumatoid factor plus complement. Dependence of the R F PFC on protein synthesis and intact microtubular excretory system was indicated by studies in which cycloheximide or vinblastine was added to the agar. In other studies the addition of propranolol also markedly reduced the number of R F PFC observed. This effect of propranolol did not seem to be explained on the basis of its ability to block 6-adrenergic receptors. This study was designed to learn more about the propranolol effect. MATERIALS AND METHODSSubjects. The human lymphocytes studied were from normal laboratory personnel or from patients with seropositive RA, high numbers of R F PFC in their blood, and erythrocyte sedimentation rates greater than 40 mm per hour.Fifty to 250 ml of each patient's blood were drawn into heparinized syringes and allowed to sediment for an hour. The leukocyte-rich plasma and top 10-20% of red cells were expressed into separate tubes and the remaining red cells then returned to the patients by intravenous infusion.Preparation of Lymphocytes from Patients. The leukocyte-red cell suspension was diluted 1 :2 in normal saline and layered in 30 ml aliquots over 12 ml of ficoll-hypaque (2).

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“…The β-amino alcohol functional motif is one of the most important pharmacophores because of its ubiquity in biologically active compounds, such as antibiotics, alkaloids, enzyme inhibitors, and β-blockers . Among the latter class, ( S )-propranolol is, for example, a well-known antihypertensive drug, whereas the ( R )-enantiomer has a contraceptive effect, one of the myriad of examples unambiguously demonstrating the need for enantiomeric purity in pharmaceuticals.…”

Section: Introductionmentioning

confidence: 99%

Resolution of Racemic 2-Aminocyclohexanol Derivatives and Their Application as Ligands in Asymmetric Catalysis

et al. 2006

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A preparatively easy and efficient protocol for the resolution of racemic 2-aminocyclohexanol derivatives is described, delivering both enantiomers with >99% enantiomeric excess (ee) by sequential use of (R)- and (S)-mandelic acid. A simple aqueous workup procedure permits the isolation of the amino alcohols in analytically pure form and the almost quantitative recovery of mandelic acid. Debenzylation of enantiopure trans-2-(N-benzyl)amino-1-cyclohexanol by hydrogenation and subsequent derivatization give access to a broad variety of diversely substituted derivatives. Furthermore, the corresponding cis isomers are readily available. Applications of these optically active aminocyclohexanols in catalyzed asymmetric phenyl transfer reactions to benzaldehydes and transfer hydrogenations of aryl ketones lead to products with up to 96% ee.

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b-Adrenergic blocking agents. Nitrogen heteroaryl-substituted 2-propanolamines and ethanolamines

Cited by 17 publications

References 4 publications

5-(2-Aminoethyl)dibenzo[c,h][1,6]naphthyridin-6-ones: Variation of N-Alkyl Substituents Modulates Sensitivity to Efflux Transporters Associated with Multidrug Resistance

5-(2-Aminoethyl)dibenzo[c,h][1,6]naphthyridin-6-ones: Variation of N-Alkyl Substituents Modulates Sensitivity to Efflux Transporters Associated with Multidrug Resistance

Drugs affecting the release of rheumatoid factor in a plaque‐forming cell assay

Resolution of Racemic 2-Aminocyclohexanol Derivatives and Their Application as Ligands in Asymmetric Catalysis

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