Strategies for Enhancing Oral Bioavailability and Brain Penetration

Shook, Brian C.; Jackson, Paul F.

doi:10.1016/b978-0-12-374194-3.00035-4

Cited by 1 publication

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References 34 publications

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“…We calculated pK a and Log P of each molecule of the set (see Supporting Information). 65 These parameters (pK a ranging 7.9−9.3 units, Log P ranging 2.3−3.5 units) are in accordance with those required for a central action, 66 which are to be compared with those of rilmenidine (pK a = 9.22; Log P = 1.63) and clonidine (pK a = 8.11; Log P = 1.59). 67 These assumptions were completed by in silico estimations of the BBB crossing capacity of compounds 1−18 and reference compounds clonidine and rilmenidine (see Supporting Information).…”

Section: ■ Chemistrymentioning

confidence: 64%

Synthesis and Biological Evaluation of 2-Aryliminopyrrolidines as Selective Ligands for I₁ Imidazoline Receptors: Discovery of New Sympatho-Inhibitory Hypotensive Agents with Potential Beneficial Effects in Metabolic Syndrome

et al. 2014

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New 2-aryliminopyrrolidines (1-18) were synthesized and tested for their binding properties on I1 imidazoline receptors vs α2-adrenergic receptors and their blood pressure effects after both systemic and intracerebral administrations. The purposes of this study were: (i) to analyze structure-activity and affinity relationships on I1 imdazoline receptors and (ii) to propose some leader compounds for the development of new sympatho-inhibitory drugs with potential applications in hypertension and/or metabolic syndrome, i.e., a cluster of cardiovascular (hypertension) and metabolic disorders. Our study highlights decisive arguments of SAR concerning both the affinity for I1Rs and the hypotensive activity of 2-aryliminopyrrolidines. Binding assays showed high affinity and selectivity of some compounds for I1 imidazoline receptors over α2-adreergic receptors. Compound 13 (laboratory reference LNP599; Ki = 3.2 nM on I1imidazoline receptors) is the prototype for the development of new centrally acting agents targeting specifically I1imidazoline receptors to be used in the management of hypertension and/or metabolic syndrome.

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Section: ■ Chemistrymentioning

confidence: 64%

Synthesis and Biological Evaluation of 2-Aryliminopyrrolidines as Selective Ligands for I₁ Imidazoline Receptors: Discovery of New Sympatho-Inhibitory Hypotensive Agents with Potential Beneficial Effects in Metabolic Syndrome

et al. 2014

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Strategies for Enhancing Oral Bioavailability and Brain Penetration

Cited by 1 publication

References 34 publications

Synthesis and Biological Evaluation of 2-Aryliminopyrrolidines as Selective Ligands for I₁ Imidazoline Receptors: Discovery of New Sympatho-Inhibitory Hypotensive Agents with Potential Beneficial Effects in Metabolic Syndrome

Synthesis and Biological Evaluation of 2-Aryliminopyrrolidines as Selective Ligands for I₁ Imidazoline Receptors: Discovery of New Sympatho-Inhibitory Hypotensive Agents with Potential Beneficial Effects in Metabolic Syndrome

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Strategies for Enhancing Oral Bioavailability and Brain Penetration

Cited by 1 publication

References 34 publications

Synthesis and Biological Evaluation of 2-Aryliminopyrrolidines as Selective Ligands for I1 Imidazoline Receptors: Discovery of New Sympatho-Inhibitory Hypotensive Agents with Potential Beneficial Effects in Metabolic Syndrome

Synthesis and Biological Evaluation of 2-Aryliminopyrrolidines as Selective Ligands for I1 Imidazoline Receptors: Discovery of New Sympatho-Inhibitory Hypotensive Agents with Potential Beneficial Effects in Metabolic Syndrome

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Synthesis and Biological Evaluation of 2-Aryliminopyrrolidines as Selective Ligands for I₁ Imidazoline Receptors: Discovery of New Sympatho-Inhibitory Hypotensive Agents with Potential Beneficial Effects in Metabolic Syndrome

Synthesis and Biological Evaluation of 2-Aryliminopyrrolidines as Selective Ligands for I₁ Imidazoline Receptors: Discovery of New Sympatho-Inhibitory Hypotensive Agents with Potential Beneficial Effects in Metabolic Syndrome