1-Benzylbenzimidazoles: The discovery of a novel series of bradykinin B1 receptor antagonists

Guo, Qin; Chandrasekhar, Jayaraman; Ihle, David C.; Wustrow, David; Chenard, B. L.; Krause, James E.; Hutchison, Alan J.; Alderman, Dawn; Cheng, Charles; Cortright, Daniel N.; Broom, Daniel C.; Kershaw, Mark T.; Simmermacher-Mayer, Jean; Peng, Yao; Hodgetts, Kevin J.

doi:10.1016/j.bmcl.2008.08.014

Cited by 11 publications

(10 citation statements)

References 17 publications

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“…80 Rationally designed using a scaffold hopping strategy, early Neurogen B1 antagonist lead compound 41 displayed encouraging potency (cynomologous macaque B1 IC 50 = 5 nM) (Figure 15). 81 Compound 41, however, had low passive permeability (1 × 10 −6 cm/s) and was determined to be a strong P-gp substrate (ER = 23) in an MDR1-MDCK assay. This finding was confirmed by testing the permeability of the compound in the presence of the P-gp inhibitor cyclosporine (25 nM), which resulted in the passive permeability of 41 increasing to 11 × 10 −6 cm/s and the ER decreasing to 1.5.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Structural Modifications that Alter the P-Glycoprotein Efflux Properties of Compounds

Hitchcock¹

2012

J. Med. Chem.

187

203

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Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Structural Modifications that Alter the P-Glycoprotein Efflux Properties of Compounds

Hitchcock¹

2012

J. Med. Chem.

187

203

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“…In most cell types, the bradykinin B2 receptor is expressed under normal conditions, whereas the bradykinin B1 receptor is expressed in infections, inflammatory diseases and traumatic tissue injury. Guo et al, in 2008, introduced a benzimidazole nucleus into a benzodiazepine derivative with potent bradykinin B1 receptor antagonistic activity, by replacing the phenethyl benzodiazepine moiety, and reported anti-inflammatory activity. Their study showed a potent antagonistic effect at bradykinin B1 receptors with better bioavailability.…”

Section: Bradykinin Receptor Antagonistsmentioning

confidence: 99%

“…They also revealed that the 2-carboxamide group on benzimidazole was necessary for the activity. Still, the activity was reduced when the ethyl linker between the two carboxamide groups was replaced with a methyl or any other longer alkyl group [ 25 ] ( Figure 10 ). They concluded that the hydrogen bond acceptor in these compounds seemed to enhance the effect.…”

Section: Structure–activity Relationships Of Benzimidazole Derivatives As Anti-inflammatory Agentsmentioning

confidence: 99%

Structure–Activity Relationship Analysis of Benzimidazoles as Emerging Anti-Inflammatory Agents: An Overview

et al. 2021

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A significant number of the anti-inflammatory drugs currently in use are becoming obsolete. These are exceptionally hazardous for long-term use because of their possible unfavourable impacts. Subsequently, in the ebb-and-flow decade, analysts and researchers are engaged in developing new anti-inflammatory drugs, and many such agents are in the later phases of clinical trials. Molecules with heterocyclic nuclei are similar to various natural antecedents, thus acquiring immense consideration from scientific experts and researchers. The arguably most adaptable heterocyclic cores are benzimidazoles containing nitrogen in a bicyclic scaffold. Numerous benzimidazole drugs are broadly used in the treatment of numerous diseases, showing promising therapeutic potential. Benzimidazole derivatives exert anti-inflammatory effects mainly by interacting with transient receptor potential vanilloid-1, cannabinoid receptors, bradykinin receptors, specific cytokines, 5-lipoxygenase activating protein and cyclooxygenase. Literature on structure–activity relationship (SAR) and investigations of benzimidazoles highlight that the substituent’s tendency and position on the benzimidazole ring significantly contribute to the anti-inflammatory activity. Reported SAR analyses indicate that substitution at the N1, C2, C5 and C6 positions of the benzimidazole scaffold greatly influence the anti-inflammatory activity. For example, benzimidazole substituted with anacardic acid on C2 inhibits COX-2, and 5-carboxamide or sulfamoyl or sulfonyl benzimidazole antagonises the cannabinoid receptor, whereas the C2 diarylamine and C3 carboxamide substitution of the benzimidazole scaffold result in antagonism of the bradykinin receptor. In this review, we examine the insights regarding the SARs of anti-inflammatory benzimidazole compounds, which will be helpful for researchers in designing and developing potential anti-inflammatory drugs to target inflammation-promoting enzymes.

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“…Also, 1‐benzylbenzimidazole 3 was described as a bradykinin (BK) B1 receptor antagonist with excellent affinity (EC 50 = 2 n m ) and 3 was used as anti‐inflammatory analgesic . In addition, bilastine 4 has shown to possess anti‐inflammatory activity .…”

mentioning

confidence: 99%

“…Compound 2 was identified as a potent 5-lipo-oxygenase-activating protein (FLAP) inhibitor (IC 50 = 0.12 lM), which is currently considered as a promising and clinically relevant strategy for pharmacological intervention with inflammatory diseases (22). Also, 1-benzylbenzimidazole 3 was described as a bradykinin (BK) B1 receptor antagonist with excellent affinity (EC 50 = 2 nM) and 3 was used as anti-inflammatory analgesic (23). In addition, bilastine 4 has shown to possess anti-inflammatory activity (24 Research Article benzimidazole is a privileged structure that can be used in drug design as anti-inflammatory agents.…”

mentioning

confidence: 99%

Discovery of Novel 2‐(piperidin‐4‐yl)‐1H‐benzo[d]imidazole Derivatives as Potential Anti‐Inflammatory Agents

Wang

et al. 2015

Chem Biol Drug Des

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A novel 2-(piperidin-4-yl)-1H-benzo[d]imidazole derivative 5 with good anti-inflammatory activity was identified from our in-house library. Based on hit compound 5, two series of 2-(piperidin-4-yl)-1H-benzo[d]imidazole derivative 6a-g and 7a-h were designed and synthesized as novel anti-inflammatory agents. Most of synthesized compounds exhibited good inhibitory activity on NO and TNF-α production in LPS-stimulated RAW 264.7 macrophages, in which the compound 6e showed most potent inhibitory activity on NO (IC50 = 0.86 μm) and TNF-α (IC50 = 1.87 μm) production. Further evaluation revealed that compound 6e displayed more potent in vivo anti-inflammatory activity than ibuprofen did on xylene-induced ear oedema in mice. Additionally, Western blot analysis revealed that compound 6e could restore phosphorylation level of IκBα and protein expression of p65 NF-κB in LPS-stimulated RAW 264.7 macrophages.

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1-Benzylbenzimidazoles: The discovery of a novel series of bradykinin B1 receptor antagonists

Cited by 11 publications

References 17 publications

Structural Modifications that Alter the P-Glycoprotein Efflux Properties of Compounds

Structural Modifications that Alter the P-Glycoprotein Efflux Properties of Compounds

Structure–Activity Relationship Analysis of Benzimidazoles as Emerging Anti-Inflammatory Agents: An Overview

Discovery of Novel 2‐(piperidin‐4‐yl)‐1H‐benzo[d]imidazole Derivatives as Potential Anti‐Inflammatory Agents

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