Expedited SAR study of high-affinity ligands to the α2δ subunit of voltage-gated calcium channels: Generation of a focused library using a solution-phase Sn2Ar coupling methodology

Chen, Chixu; Stearns, Brian A.; Hu, Tao; Anker, Naomi; Santini, Angelina M.; Arruda, Jeannie M.; Campbell, Brian T.; Datta, Purabi; Aiyar, Jayashree; Munoz, Benitio

doi:10.1016/j.bmcl.2005.08.117

Cited by 15 publications

(10 citation statements)

References 19 publications

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“…5 A second way that data is frequently analyzed, particularly with regard to potency, is that a few matched pairs of molecules that differ only by a small structural change (a matched molecular pair) will be identified and the corresponding change in potency calculated. 6 This is most commonly used to breakdown SAR into manageable structural components and such matched structures can be designed systematically according to the Free-Wilson approach. 7 As demonstrated previously, the analysis can be used to study effects in ADME (absorption, distribution, metabolism, and excretion) and physical properties in a more generic fashion.…”

Section: Introductionmentioning

confidence: 99%

Matched Molecular Pairs as a Guide in the Optimization of Pharmaceutical Properties; a Study of Aqueous Solubility, Plasma Protein Binding and Oral Exposure

et al. 2006

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By identifying every pair of molecules that differ only by a particular, well-defined, structural transformation in a database of measured properties and computing the corresponding change in property, we obtain an overview of the effect that structural change has upon the property and set an expectation for what will happen when that transformation is applied elsewhere. The mean change indicates the expected magnitude of the change in the property and the number of cases in which the property increases give the probability that the structural transformation will cause the property to increase. Outliers indicate potential ways of avoiding the general trend. Comparing to changes in lipophilicity highlights structural transformations that have unusual effects, some of which can be explained by conformational changes. In this paper, we focus upon the effects on aqueous solubility, plasma protein binding and oral exposure of adding substituents to aromatic rings and methylating heteroatoms.

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Section: Introductionmentioning

confidence: 99%

Matched Molecular Pairs as a Guide in the Optimization of Pharmaceutical Properties; a Study of Aqueous Solubility, Plasma Protein Binding and Oral Exposure

et al. 2006

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“…N-Ethyl-9-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin-2-amine (21). To a solution of compound 20 (227 mg, 0.73 mmol) in DCM (4 mL), m-CPBA (252 mg, 1.46 mmol) was added, and the mixture was stirred at rt for 3.5 h. NaHCO 3 saturated solution was added, and the mixture was extracted with DCM.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…A few nonaminoacidic structures have also been reported, but none of them have progressed into clinical development. Among others, , Merck reported several Ca v α2δ-1 ligands represented by compound 4 , − a structure that was later modified by GlaxoSmithKline to afford compounds such as 5 , which showed good analgesic activity in the complete Freund’s adjuvant pharmacodynamic model of pain. Finally, Kyowa Hakko Kirin Co., filed two patent families, , describing pyrimidodiazepinone tricyclic derivatives represented by compound 6 .…”

Section: Introductionmentioning

confidence: 99%

Bicyclic Diazepinones as Dual Ligands of the α2δ-1 Subunit of Voltage-Gated Calcium Channels and the Norepinephrine Transporter

et al. 2021

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The synthesis and pharmacological activity of a new series of bicyclic diazepinones with dual activity toward the α2δ-1 subunit of voltage-gated calcium channels (Ca v α2δ-1) and the norepinephrine transporter (NET) are reported. Exploration of the positions amenable for substitution on a nonaminoacidic Ca v α2δ-1 scaffold allowed the identification of favorable positions for the attachment of NET pharmacophores. Among the patterns explored, attachment of the 2-ethylamino-9-methyl-6-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin-5-one framework to the meta-position of the phenyl ring of the 3methylamino-1-phenylpropoxy and 3-methylamino-1-thiophenylpropoxy moieties provided dual compounds with excellent NET functionality. Alternative bicyclic frameworks were also explored, and some lead molecules were identified, which showed a balanced dual profile and exhibited good ADMET properties.

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“…Treatment of ester (243), aldehyde or ketone (245) substituted 3-acetylpyrroles with hydrazine in ethanol results in the formation of a wide range of substituted pyrrole fused pyridazines (Scheme 65). [101][102][103] These compounds were identified as high affinity ligands for the a2d subunit of voltage gated calcium channels (gabapentin binding site). The lead compounds of this series displayed IC 50 values in the range of 20-50 nM.…”

Section: Condensation Of Aptly Substituted Pyrrolesmentioning

confidence: 99%

Synthesis of isoindoles and related iso-condensed heteroaromatic pyrroles

2012

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Over the past few years, isoindoles have found wide application in materials science. Isoindole containing BODIPY dyes are highly fluorescent materials and have been extensively used in various fields of science. Phthalocyanines, metal containing cyclic tetramers of isoindole, form coordination complexes with most elements of the periodic table. These complexes are intensely coloured and are used as pigments and dyes. However, isoindoles are relatively unstable 10π-heteroaromatic systems and few synthetic methods provide these compounds in good yields. This tutorial review will give an overview of the reported synthetic methods towards isoindoles and related heteroaromatic systems over a time span of approximately 10 years (2000 to current), including the applications where they have been reported. The importance of the field will be illustrated and factors influencing product stability will be discussed.

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Expedited SAR study of high-affinity ligands to the α2δ subunit of voltage-gated calcium channels: Generation of a focused library using a solution-phase Sn2Ar coupling methodology

Cited by 15 publications

References 19 publications

Matched Molecular Pairs as a Guide in the Optimization of Pharmaceutical Properties; a Study of Aqueous Solubility, Plasma Protein Binding and Oral Exposure

Matched Molecular Pairs as a Guide in the Optimization of Pharmaceutical Properties; a Study of Aqueous Solubility, Plasma Protein Binding and Oral Exposure

Bicyclic Diazepinones as Dual Ligands of the α2δ-1 Subunit of Voltage-Gated Calcium Channels and the Norepinephrine Transporter

Synthesis of isoindoles and related iso-condensed heteroaromatic pyrroles

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