Synthesis and SAR studies of benzimidazole derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists: Focus to detune hERG inhibition

Sasmal, Pradip K.; Sasmal, Sanjita; Abbineni, Chandrasekhar; Venkatesham, B.; Rao, P. Tirumala; Roshaiah, M.; Khanna, Ish; Sebastián, Víctor; Joghee, Suresh; Singh, Manvendra; Talwar, Rashmi; Shashikumar, Dhanya; Reddy, K. Harinder; Frimurer, Thomas M.; Rist, Øystein; Elster, Lisbeth; Högberg, Thomas

doi:10.1039/c1md00015b

Cited by 14 publications

(10 citation statements)

References 34 publications

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“…Among these GW 856464 [211], AMG076 [212] and NGD-4715 [213] achieved phase 1 clinical investigations. Trials to optimize quinazolines [214][215][216][217][218][219], as (40) (Figure 9(a)), revealed GW 803430 (GW3430; [214]), ATC0175 and ATC0065 [215] which were shown efficacious in rodent depression models [197]. However, ATC0175 and ATC0065 are binding with high affinity not only to MCH1-R but also to subtypes of the 5 HT receptor [197] suggesting that the antidepressiv effect of the MCH1-R antagonist is not due to MCH1-R alone.…”

Section: Non-peptide Ligands Of Mch-receptorsmentioning

confidence: 99%

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

Pissarek¹,

Disko²

2013

WJNS

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Hypothalamic receptors for neuropeptide Y, melaninconcentrating hormone, melanocortins and orexins/ hypocretins as well as for the downstream signaling corticotrophic factor have been discussed broadly for their influence on food intake and reward but also on several psychiatric disorders. For the development of non-peptide ligands for the in vivo detection of alterations in density and affinity of such G-protein coupled (GPCRs) peptide receptors the requirements to affinity and pharmacokinetics have been shifted to thresholds markedly distict from classical GPCRs to dissociation constants < 0.5 nM, partition coefficients log P < 3.5 and transcellular transport ratios, e.g. for the permeability glycoprotein transporter, below 3. Nevertheless, a multitude of compounds has been reported originally as potential therapeutics in the treatment of obesity among which some are suitable candidates for labeling as PET or SPECT-tracers providing receptor affinities even below 0.1 nM. These could be unique tools not only for better understanding of the mechanism of obesity but also for investigations of extrahypothalamic role of "feeding receptors" at the interface between neuroendocrine and mental diseases.

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Section: Non-peptide Ligands Of Mch-receptorsmentioning

confidence: 99%

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

Pissarek¹,

Disko²

2013

WJNS

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“…Functionalization of C‐2 position is another possible method to achieve 1,2‐disubstituted benzimidazoles 33. During their recent work towards the synthesis of melanin hormone receptor 1 antagonists, Högberg and co‐workers described the synthesis of some benzimidazole intermediates by acylation of the 2‐position with the Weinreb amide in the presence of LDA (lithium diisopropylamide) to afford the desired compounds (Scheme ) 33a…”

Section: Functionalization Of the Benzimidazole Ringmentioning

confidence: 99%

Developments Towards Regioselective Synthesis of 1,2‐Disubstituted Benzimidazoles

Carvalho

Fernandes

Marques

2011

Chemistry A European J

143

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1,2-Disubstituted benzimidazoles play an important role in several areas and particularly as drug discovery targets. Herein, several methods to assemble these structures are reviewed, from the classical approaches to the more recently developed metal-catalyzed intramolecular amination process, the cascade arylamination/condensation reaction and polymer-supported benzimidazole assembly under microwave conditions.

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“…For details of the synthesis and related structures, see: Wright (1951); Preston (1974); Hamzah et al (2010); Arumugam et al 2011); Ruiz et al (2010); Chou et al (2011). For the therapeutic properties of benzimidazole derivatives, see: Li et al (2006); Hwu et al (2008); Cui et al (2010); Sasmal et al (2011); Demirayak et al (2011). For bond lengths in organic compounds, see: Allen et al (1987).…”

Section: Related Literaturementioning

confidence: 99%

“…Data collection: APEX2 (Bruker, 2009); cell refinement: SAINT (Bruker, 2009); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Sheldrick, 2008); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL and PLATON (Spek, 2009 (Sasmal et al, 2011), probes for β-amyloid (Aβ) plaques in Alzheimer's disease (Cui et al, 2010), showed anti-cancer activities (Demirayak et al, 2011), anti hepatitis B (Li et al, 2006) and C virus (Hwu et al, 2008). Various methods have been employed to synthesize benzimidazole derivatives (Wright, 1951;Preston, 1974).…”

Section: Data Collectionmentioning

confidence: 99%

Ethyl 1-(2-hydroxyethyl)-2-[2-(methylsulfanyl)ethyl]-1H-benzimidazole-5-carboxylate

et al. 2011

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In the crystal structure of the title compound, C15H20N2O3S, the hydroxy group is involved in the formation of O—H⋯N hydrogen bonds, which link two molecules into a centrosymmetric dimer. Weak C—H⋯O hydrogen bonds further link these dimers into chains propagating along the a axis. The crystal packing exhibits π–π interactions between the five- and six-membered rings of neighbouring molecules [centroid–centroid distance = 3.819 (2) Å] and short intermolecular S⋯S contacts of 3.495 (1) Å.

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Synthesis and SAR studies of benzimidazole derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists: Focus to detune hERG inhibition

Cited by 14 publications

References 34 publications

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

Developments Towards Regioselective Synthesis of 1,2‐Disubstituted Benzimidazoles

Ethyl 1-(2-hydroxyethyl)-2-[2-(methylsulfanyl)ethyl]-1H-benzimidazole-5-carboxylate

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