6-Acylamino-2-aminoquinolines as Potent Melanin-Concentrating Hormone 1 Receptor Antagonists. Identification, Structure−Activity Relationship, and Investigation of Binding Mode

Abstract

Novel 6-acylamino-2-aminoquinoline melanin-concentrating hormone 1 receptor (MCH1R) antagonists were identified by sequential in silico screening with 3D pharmacophore models derived from a series of benzamide antagonists. The structure-activity relationship exploration by synthesis of analogues found structural demands around the western part of the compounds to be quite specific, whereas much structural freedom was found in the eastern part. While these compounds in general suffered from poor solubility properties, the 4-trifluoromethoxyphenoxyacetamide western appendage provided a favorable combination of activity and solubility properties. The amine in the eastern appendage, originally required by the pharmacophore model and believed to interact with Asp123 in transmembrane 3 of MCH1R, could be removed without diminishing affinity or functional activity of the compounds. Docking studies suggested that the Asp123 interacts preferentially with the nitrogen of the central quinoline. Synthesis and testing of specific analogues supported our revised binding mode hypothesis.

G Protein Coupled Receptors - In Silico Drug Discovery and Design

“…MCH1 receptor screening was performed by Ulven et al, using a set of HypoGen pharmacophore hypotheses [38]. Twenty five 3D pharmacophore hypotheses were generated based on 42 representative known ligands of the same scaffold.…”

Anti-obesity effects of small molecule melanin-concentrating hormone receptor1 (MCHR1) antagonists

“…7TM Pharma recently published a series of papers describing the discovery and optimization of their aminomethylquinoline and ureidobenzamide series (Receveur et al, 2004;Ulven et al, 2005;Ulven et al, 2006). Although this group was able to produce low nanomolar affinity compounds such as compounds 8 and 9 (See Fig.…”

MCH-R1 Antagonists as Potential Anti-obesity Drugs. Design Strategies and Structure-activity Relationship

“…46 Thus, modification of the benzamide group in bicyclic derivatives retaining a carbonyl group, was proposed as an effective strategy for minimizing clearance of the compounds. 47 However, in the case of the fused benzopyridazinones ring as compound 6 (Figure 8), the improved pharmacokinetics was also associated with some untoward partitioning of the compound into tissues and very high brain penetration. 48 Later, they showed a series of substituted chromones (compound 7, Figure 8) with subnanomolar binding affinity and 66% oral bioavailability in rats.…”

“…antagonists; their design was structure-based on biphenyl carboxy group replacements suggesting key pharmacophoric points (a tertiary amine, an amide bond and a terminal aromatic ring of the biphenyl group) for biological activity. 47 Compound 9 ( Figure 10) showed its potential as an effective orally dosed MCH-R1 antagonist. Unfortunately, compound 9 was compromised by its hERG blockage activity, leading to an observed dose-dependent increase in QT interval in anesthetized dogs at serum concentrations comparable to those obtained at efficacious doses.…”