Structure-Lipophilicity Relationships of Neutral and Protonatedβ-Blockers, Part I, Intra- and Intermolecular Effects in Isotropic Solvent Systems

Caron, Giulia; Steyaert, Guillaume; Pagliara, Alessandra; Reymond, Frédéric; Crivori, Patrizia; Gaillard, Patrick; Carrupt, Pierre‐Alain; Avdeef, Alex; Comer, John; Box, Karl; Girault, Hubert H.; Testa, Bernard

doi:10.1002/(sici)1522-2675(19990804)82:8<1211::aid-hlca1211>3.0.co;2-k

Cited by 91 publications

(56 citation statements)

References 9 publications

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“…This approach was applied to logP data available from the literature in cyclohexane/water 25 and 1,2-dichloroethane/water systems 29,45 and it revealed the same trends; data shown in Supporting Information (Annex S3).…”

Section: Figure 3 Examples Of Cosmo-rs Results For Conformations Of mentioning

confidence: 99%

Integrating Intramolecular Hydrogen Bonding (IMHB) Considerations in Drug Discovery Using ΔlogP As a Tool

et al. 2013

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This study demonstrates that logP oct-tol (difference between logPoctanol and logPtoluene) describes compounds propensity to form intramolecular hydrogen bonds (IMHB) and may be considered a privileged molecular descriptor for use in drug discovery and for prediction of IMHB in drug candidates.We identified experimental protocols for acquiring reliable logP oct-tol values on a set of compounds representing IMHB motifs most prevalent in Medicinal Chemistry, mainly molecules capable of forming 6-, 7-member IMHB rings.Furthermore, computational logP oct-tol values obtained with COSMO-RS software provided a good estimate of experimental results and can be used prospectively to assess IMHB.The proposed interpretation method based on logP oct-tol data allowed categorization of the compounds into 2 groups -with high propensity to form IMHB and poor propensity or poor relevance of IMHB.The relative 1 H NMR chemical shift of an exchangeable proton was used to verify presence of IMHB and to validate the IMHB interpretation scheme.4

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Section: Figure 3 Examples Of Cosmo-rs Results For Conformations Of mentioning

confidence: 99%

Integrating Intramolecular Hydrogen Bonding (IMHB) Considerations in Drug Discovery Using ΔlogP As a Tool

et al. 2013

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“…The reason for the unexpected finding that the ligands with poor agonistic activity were less able to stabilize hb 1 ARs is not known. The reason is unlikely to be differences in hydrophobicity, as no correlation was detected between the ability of the compounds to stabilize the receptors and their partition coefficient (log P) and topological polar surface area values (Supplemental Table 3), which describe ligand behavior in a lipid environment (Hellenbrecht et al, 1973;Caron et al, 1999). It can be speculated that the answer lies in the different ability of the ligands to elicit conformational changes in the receptor and the possibility that the active conformation stabilized by the agonists might be more stable than that of the antagonist/inverse agonist--stabilized inactive conformation.…”

Section: Discussionmentioning

confidence: 99%

β-Adrenergic Agonists Mediate Enhancement of β1-Adrenergic Receptor N-terminal Cleavage and Stabilization In Vivo and In Vitro

Hakalahti¹,

Khan²,

Vierimaa³

et al. 2013

Molecular Pharmacology

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The b 1 -adrenergic receptor (b 1 AR) is the predominant bAR in the heart and is the main target for b-adrenergic antagonists, widely used in the treatment of cardiovascular diseases. Previously, we have shown that the human (h) b 1 AR is cleaved in its N terminus by a metalloproteinase, both constitutively and in a receptor activation-dependent manner. In this study, we investigated the specific events involved in b 1 AR regulation, focusing on the effects of long-term treatment with b-adrenergic ligands on receptor processing in stably transfected human embryonic kidney 293 i cells. The key findings were verified using the transiently transfected hb 1 AR and the endogenously expressed receptor in neonatal rat cardiomyocytes. By using flow cytometry and Western blotting, we demonstrated that isoproterenol, S-propranolol, CGP-12177 [4-[3-[(1,1-dimethylethyl)amino]2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one], pindolol, and timolol, which displayed agonistic properties toward the b 1 AR in either the adenylyl cyclase or the mitogen-activated protein kinase signaling pathways, induced cleavage of the mature cell-surface receptor. In contrast, metoprolol, bisoprolol, and CGP-20712 [1-[2-((3-carbamoyl-4-hydroxy) phenoxy)ethylamino]-3-[4-(1-methyl-4-trifluoromethyl-2-imidazolyl) phenoxy]-2-propanol], which showed no agonistic activity, had only a marginal or no effect. Importantly, the agonists also stabilized intracellular receptor precursors, possibly via their pharmacological chaperone action, and they stabilized the receptor in vitro. The opposing effects on the two receptor forms thus led to an increase in the amount of cleaved receptor fragments at the plasma membrane. The results underscore the pluridimensionality of b-adrenergic ligands and extend this property from receptor activation and signaling to the regulation of b 1 AR levels. This phenomenon may contribute to the exceptional resistance of b 1 ARs to downregulation and tendency toward upregulation following long-term ligand treatments.

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“…However, that output was one magnitude down compared to those of the CRV standard drug (the pKa=7.97; Caron et al, 1999).…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, the most of the β-AdrAs (acebutolol, alprenolol, atenolol, and carazolol, for example) has shown similar values of the pKa of around 9.50 (Caron et al, 1999). The origin of thus discrepancy in the pKas between carvedilol and the other β--AdrAs was attributed to an inductive effect of a β-O-atom, which lowered the basicity of an amino group.…”

Section: Introductionmentioning

confidence: 81%

“…Following physicochemical properties of the mentioned compounds, carvedilol was considered slightly more basic with potentiometrically estimated dissociation constant (pKa) of 7.97 (Caron et al, 1999) than the substances 1-4, which pKas were found in the interval of 5.83 (the compound 3) to 6.73 (1), as published by Malík et al (2005;. On the other hand, the most of the β-AdrAs (acebutolol, alprenolol, atenolol, and carazolol, for example) has shown similar values of the pKa of around 9.50 (Caron et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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The in Vitro Antioxidant Properties of 2-Alkoxyphenylcarbamic Acid Derivatives Containing a 4´-(Substituted Phenyl)piperazin-1´-Yl Moiety Determined by the 2,2´-Azinobis(3-Ethylbenzothiazoline-6-Sulfonic Acid) Derived Radical Cation (Abts•+) and Ferric Re

Malík

Stanzel

Csöllei

et al. 2017

Indonesian J. Pharm.

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In an effort to comprehensively characterize an antioxidant profile of 2-alkoxyphenylcarbamic acid-based compounds containing a 4´-(substituted phenyl)piperazin-1´-yl fragment, they were in vitro screened in the 2,2´-azino-bis(3-ethylbenzothiazoline-6--sulfonic acid) derived radical cation (ABTS •+ ) and ferric reducing antioxidant power (FRAP) assay using the UV/VIS spectrophotometry. The ABTS•+ scavenging (reducing) potential of 1-[3-(2-methoxyphenylcarbamoyl)oxy-2-hydroxypropyl]-4-(4--fluorophenyl)piperazin-1-ium chloride was found to be the most promising and it was comparable to the efficiency of the carvedilol reference drug. Moreover, that 4´-fluoro group-containing compound was regarded as more active than the atenolol standard. When testing the molecules´ power to reduce the ferric 2,4,6-tris (2-pyridyl)-s-triazine complex [Fe(III)(TPTZ) 2 ] 3+ , the most prospective was 1-[3-(2-ethoxyphenylcarbamoyl)oxy-2--hydroxypropyl]-4-(4-fluorophenyl)piperazin-1-ium chloride. On the other hand, its Fe 3+ reducing power was lower compared to both standards carvedilol and atenolol. The study discussed structure-antioxidant properties relationships considering electronic, steric and lipophilic features.

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Structure-Lipophilicity Relationships of Neutral and Protonatedβ-Blockers, Part I, Intra- and Intermolecular Effects in Isotropic Solvent Systems

Cited by 91 publications

References 9 publications

Integrating Intramolecular Hydrogen Bonding (IMHB) Considerations in Drug Discovery Using ΔlogP As a Tool

Integrating Intramolecular Hydrogen Bonding (IMHB) Considerations in Drug Discovery Using ΔlogP As a Tool

β-Adrenergic Agonists Mediate Enhancement of β1-Adrenergic Receptor N-terminal Cleavage and Stabilization In Vivo and In Vitro

The in Vitro Antioxidant Properties of 2-Alkoxyphenylcarbamic Acid Derivatives Containing a 4´-(Substituted Phenyl)piperazin-1´-Yl Moiety Determined by the 2,2´-Azinobis(3-Ethylbenzothiazoline-6-Sulfonic Acid) Derived Radical Cation (Abts•+) and Ferric Re

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