Synthesis and sar of 4-(1H-benzimidazole-2-carbonyl)piperidines with dual histamine H1/tachykinin NK1 receptor antagonist activity

Maynard, George D.; Bratton, Larry; Kane, John M.; Burkholder, Timothy P.; Santiago, Braulio; Stewart, Kenneth T.; Kudlacz, Elizabeth M.; Shatzer, S. A.; Knippenberg, Robert W.; Farrell, Amy M.; Logan, Deborah E.

doi:10.1016/s0960-894x(97)10097-x

Cited by 16 publications

(2 citation statements)

References 7 publications

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“…Dual-acting drugs for activation of multiple receptors, even if not targeting GPCR dimers, have become important in drug development, for example, the antipsychotic agent ziprasidone was designed with separate pharmacophores to antagonize both the D2 dopamine receptor and the 5-HT 2 serotonin receptors [128]. Combined ligands for the H1 histamine receptor and the 5-HT 2 serotonin receptors have been studied [129]. …”

Section: Functionalized Congeners Of Ligands For Other Gpcrs and Non-mentioning

confidence: 99%

Functionalized Congener Approach to the Design of Ligands for G Protein-Coupled Receptors (GPCRs)

Jacobson

2009

Bioconjugate Chem.

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Functionalized congeners, in which a chemically functionalized chain is incorporated at an insensitive site on a pharmacophore, have been designed from the agonist and antagonist ligands of various G protein-coupled receptors (GPCRs). These chain extensions enable a conjugation strategy for detecting and characterizing GPCR structure and function and pharmacological modulation. The focus in many studies of functionalized congeners has been on two families of GPCRs: those responding to extracellular purines and pyrimidines-i.e., adenosine receptors (ARs) and P2Y nucleotide receptors. Functionalized congeners of small-molecule as ligands for other GPCRs and non-G protein coupled receptors have also been designed. For example, among biogenic amine neurotransmitter receptors, muscarinic acetylcholine receptor antagonists and adrenergic receptor ligands have been studied with a functionalized congener approach. Adenosine A 1 , A 2A , and A 3 receptor functionalized congeners have yielded macromolecular conjugates, irreversibly binding AR ligands for receptor inactivation and crosslinking, radioactive probes that use prosthetic groups, immobilized ligands for affinity chromatography, and dual-acting ligands that function as binary drugs. Poly(amidoamine) dendrimers have served as nanocarriers for covalently conjugated AR functionalized congeners. Rational methods of ligand design derived from molecular modeling and templates have been included in these studies. Thus, the design of novel ligands, both small molecules and macromolecular conjugates, for studying the chemical and biological properties of GPCRs have been developed with this approach, has provided researchers with a strategy that is more versatile than the classical medicinal chemical approaches.

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Section: Functionalized Congeners Of Ligands For Other Gpcrs and Non-mentioning

confidence: 99%

Functionalized Congener Approach to the Design of Ligands for G Protein-Coupled Receptors (GPCRs)

Jacobson

2009

Bioconjugate Chem.

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“…The possibility that combined blockade of H 1 and NK 1 receptors might produce added therapeutic benefit led to the exploration of dual inhibitors by Maynard et al 68 On the basis of an understanding of the SARs for H 1 and NK 1 antagonists such as 76 and 77, it was predicted that hybrid structures such as 78 would retain NK 1 affinity (Figure 26). The compounds from this series were subjected to CoMFA analsis.…”

Section: Histamine H 1 Receptor-based Dmls For Allergiesmentioning

confidence: 99%

Designed Multiple Ligands. An Emerging Drug Discovery Paradigm

Morphy¹,

Rankovic²

2005

J. Med. Chem.

1,083

819

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Synthesis of 1,2‐Disubstituted Benzimidazoles by a Cu‐Catalyzed Cascade Aryl Amination/Condensation Process

Zou

Yuan

2007

Angewandte Chemie

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Hilfsbereite Nachbarn: Eine Vielzahl an 1,2‐disubstituierten Benzimidazolen ist aus 2‐Halogenaniliden und primären Aminen durch eine kupferkatalysierte Aminierung zugänglich, die durch die NHCOR‐Gruppe in ortho‐Stellung begünstigt wird (siehe Schema, DMSO=Dimethylsulfoxid). Die Reaktion gelingt mit vielfältigen Substituenten X in verschiedenen Positionen des Benzimidazol‐Phenylrings.

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Synthesis and sar of 4-(1H-benzimidazole-2-carbonyl)piperidines with dual histamine H1/tachykinin NK1 receptor antagonist activity

Cited by 16 publications

References 7 publications

Functionalized Congener Approach to the Design of Ligands for G Protein-Coupled Receptors (GPCRs)

Functionalized Congener Approach to the Design of Ligands for G Protein-Coupled Receptors (GPCRs)

Designed Multiple Ligands. An Emerging Drug Discovery Paradigm

Synthesis of 1,2‐Disubstituted Benzimidazoles by a Cu‐Catalyzed Cascade Aryl Amination/Condensation Process

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