Potent benzimidazolone based human β3-adrenergic receptor agonists

Finley, Don R.; Bell, Mike; Borel, Anthony G.; Bloomquist, William; Cohen, Marlene L.; Heiman, Mark L.; Kriauciunas, Aidas; Matthews, Donald P.; Miles, Tania; Neel, David A.; Rito, Christopher J.; Sall, Daniel J.; Shuker, Anthony J.; Stephens, T.; Tinsley, Frank C.; Winter, Mark A.; Jesudason, Cynthia D.

doi:10.1016/j.bmcl.2006.08.010

Cited by 8 publications

(4 citation statements)

References 25 publications

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“…In order to investigate the binding modes of different β-receptor ligands and their molecular recognitions in different local and/or distal microdomains leading to the particular subtype-selectivity, a diverse class of reported potent and selective β 3 -AR agonists, covering most of the reported chemotypes − (Figure ), and the only one selective antagonist were chosen for systematic docking studies into the binding site of homology mzodeled β 3 -AR using Glide module implemented in Schrödinger package. In addition, these ligands were also docked and scored into the binding site of high-resolution crystal structures of β 1 - and β 2 -AR and then compared with the poses of these ligands into the binding site of β 3 -AR.…”

Section: Resultsmentioning

confidence: 99%

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Structural Basis for the β-Adrenergic Receptor Subtype Selectivity of the Representative Agonists and Antagonists

Roy

Saxena

2011

J. Chem. Inf. Model.

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The β(3)-adrenegic receptor (β(3)-AR) selectivity over β(1)- and β(2)-ARs has been the most important aspect for successful therapeutic agents for obesity and type-II diabetes, as the concomitant activation of β(1)- and β(2)-ARs would lead to undesirable side effects, such as increased heart rate. In order to explore the structural basis for the β-AR subtype selectivity of agonists and anatagonists, a three-dimensional structure of until date unresolved β(3)-AR has been modeled, compared with the resolved X-ray structures of β(1)- and β(2)-ARs, and used to study its stereoselective binding with until-date known diverse classes of representative agonists and antagonist. The obtained binding structures and calculated prime molecular mechanics-generalized Born surface area (MM-GBSA) binding free energies consistently reveal that while the subtype selectivity is strongly governed by the residues present in the extracellular ends of TM3, TM5, TM6, TM7 helices and of the ECL2 domain, the binding affinity is governed by the conserved residues present in the deep pocket limiting the degree of conformational and rotational freedoms to the bound ligand. The study demonstrates that the key structural requirements for the β(3)-selectivity are: (i) a negatively ionizable group (NIG) for direct interaction with β(3)-specific residue R315(6.58), (ii) a linker (9-10 Å length) between the protonated amine and NIG, and (iii) a substituted aryl ring directly attached to the β-hydroxyl carbon. The new computational insights acquired in this study are expected to be valuable in structure-based rational design of high-affinity agonists and antagonists with pronounced β(3)-selectivity for successful therapeutic agents for type-II diabetes and obesity.

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Section: Resultsmentioning

confidence: 99%

“…Highly selective β 3 -AR agonists (1–12) and antagonist (13) covering wide structural diversity collected from the literature. − *Agonistic/antagonistic activities not found in the literature.…”

Section: Resultsmentioning

confidence: 99%

Structural Basis for the β-Adrenergic Receptor Subtype Selectivity of the Representative Agonists and Antagonists

Roy

Saxena

2011

J. Chem. Inf. Model.

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“…In some examples o-and p-hydroxymethylphenols may play a role of the quinon methide precursors. This examples are usually limited to the reaction with C-nucleophiles like base-activated 2-nitropropane [12] or potassium cyanide [13]. Reactions of pyridoxine with different alcohols are described yielding corresponding 4' -esters [14].…”

Section: Resultsmentioning

confidence: 99%

Synthetic route optimization of Sumepirin antiepileptic drug candidate

Dzyurkevich

Shtyrlin

2020

Chim.Tech.Acta

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In this work we describe the transformation of synthetic route of the antiepileptic drug candidate Sumepirin starting from discovery stage. Initial method included six step process requiring two steps of purification using colon chromatography and has poor overall yield of target compound. The process developed is convenient, scalable, technological and meet the most of conditions of green chemistry. The overall yield was increased up to 62.5% in four steps without colon chromatography purification which allows to obtain the target compound with purity of 99.5+% which is especially important for the active ingredient.

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“…Benzimidazolones play an important role in many aspects of research and synthesis such as drug discovery, bioactive chemicals, material science, and organic intermediates. They can be used as small molecular inhibitors for various therapeutic targets such as CRF1 Receptor A, 1 G1-phase, 2 histamine H3-receptor, 3 Hsp90, 4 human beta 3-adrenergic, 5 p38, 6 chymase, 7 CB2, 8 and CGRP receptor antagonist (Fig. 1).…”

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confidence: 99%