Synthesis and SAR study of pyrrolo[3,4-b]pyridin-7(6H)-one derivatives as melanin concentrating hormone receptor 1 (MCH-R1) antagonists

Lim, Chae Jo; Kim, Ji Young; Lee, Byung Ho; Oh, Kwang‐Seok; Yi, Kyu Yang

doi:10.1016/j.bmcl.2013.01.053

Cited by 9 publications

(6 citation statements)

References 25 publications

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“…The xanthone analogue 1a without isoprenyl groups at the C2 and C8 positions was synthesized via the condensation of 2,4dihydroxybenzoic acid and phloroglucinol in the presence of Eaton's reagent. 22 Then bis-α,ω-dibromoalkane-substituted xanthone 2a was synthesized using a Williamson ether synthesis followed by an amination reaction with diethylamine to form compound 3a. To synthesize tetrahydro-α-mangostin 1b, the double bonds of the isoprenyl groups were reduced by catalytic hydrogenation using a protocol similar to that previously reported by Sudta et al 23 Compounds 2b and 3b were prepared from 1b using similar protocols as for the preparation of 2a and 3a.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Amino Acid Modified Xanthone Derivatives: Novel, Highly Promising Membrane-Active Antimicrobials for Multidrug-Resistant Gram-Positive Bacterial Infections

et al. 2014

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Antibiotic resistance is a critical global health care crisis requiring urgent action to develop more effective antibiotics. Utilizing the hydrophobic scaffold of xanthone, we identified three components that mimicked the action of an antimicrobial cationic peptide to produce membrane-targeting antimicrobials. Compounds 5c and 6, which contain a hydrophobic xanthone core, lipophilic chains, and cationic amino acids, displayed very promising antimicrobial activity against multidrug-resistant Gram-positive bacteria, including MRSA and VRE, rapid time-kill, avoidance of antibiotic resistance, and low toxicity. The bacterial membrane selectivity of these molecules was comparable to that of several membrane-targeting antibiotics in clinical trials. 5c and 6 were effective in a mouse model of corneal infection by S. aureus and MRSA. Evidence is presented indicating that 5c and 6 target the negatively charged bacterial membrane via a combination of electrostatic and hydrophobic interactions. These results suggest that 5c and 6 have significant promise for combating life-threatening infections.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Amino Acid Modified Xanthone Derivatives: Novel, Highly Promising Membrane-Active Antimicrobials for Multidrug-Resistant Gram-Positive Bacterial Infections

et al. 2014

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“…The statistical significance of the preference for ≥3-fold decreases in rat clearance ( p -value = 0.002) is slightly stronger than that for all 218 MMPs associated with the clearance analysis for the 4-fluoro-analogues in Figure ( p -value = 0.009). The most favorable rat clearance result for 4-fluoro-analogues was found for a MMP of melanin concentrating hormone receptor 1 antagonists . This MMP exhibits a 16-fold decrease in rat clearance along with an equally impressive increase in oral bioavailability ( F : 35% → 93%).…”

Section: Discussionmentioning

confidence: 98%

“…The most favorable rat clearance result for 4-fluoro-analogues was found for a MMP of melanin concentrating hormone receptor 1 antagonists. 33 This MMP exhibits a 16-fold decrease in rat clearance along with an equally impressive increase in oral bioavailability (F: 35% → 93%). In contrast, the most unfavorable rat clearance result for 4-fluoro-analogues was observed for a MMP of ghrelin receptor agonists.…”

Section: ■ Introductionmentioning

confidence: 98%

Positional Analogue Scanning: An Effective Strategy for Multiparameter Optimization in Drug Design

et al. 2020

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Minimizing the number and duration of design cycles needed to optimize hit or lead compounds into high-quality chemical probes or drug candidates is an ongoing challenge in biomedical research. Small structure modifications to hit or lead compounds can have meaningful impacts on pharmacological profiles due to significant effects on molecular and physicochemical properties and intra- and intermolecular interactions. Rapid pharmacological profiling of an efficiently prepared series of positional analogues stemming from the systematic exchange of methine groups with heteroatoms or other substituents in aromatic or heteroaromatic ring-containing hit or lead compounds is one approach toward minimizing design cycles (e.g., exchange of aromatic or heteroaromatic CH groups with N atoms or CF, CMe, or COH groups). In this Perspective, positional analogue scanning is shown to be an effective strategy for multiparameter optimization in drug design, whereby substantial improvements in a variety of pharmacological parameters can be achieved.

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“…Previously, we developed novel MCHR1 antagonists such as 2-arylbenzimidazole derivatives [ 6 ], 4-arylphtalazin-1(2h)-one derivatives [ 7 ], and pyrrolo(3,4-b)pyridine-7(6H)-one derivatives [ 8 ]. These compounds strongly antagonize the MCHR1 receptor with highly potent and favorable pharmacokinetics.…”

Section: Introductionmentioning

confidence: 99%

Identification and New Indication of Melanin-Concentrating Hormone Receptor 1 (MCHR1) Antagonist Derived from Machine Learning and Transcriptome-Based Drug Repositioning Approaches

Lim

You

Lee

et al. 2022

IJMS

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Melanin-concentrating hormone receptor 1 (MCHR1) has been a target for appetite suppressants, which are helpful in treating obesity. However, it is challenging to develop an MCHR1 antagonist because its binding site is similar to that of the human Ether-à-go-go-Related Gene (hERG) channel, whose inhibition may cause cardiotoxicity. Most drugs developed as MCHR1 antagonists have failed in clinical development due to cardiotoxicity caused by hERG inhibition. Machine learning-based prediction models can overcome these difficulties and provide new opportunities for drug discovery. In this study, we identified KRX-104130 with potent MCHR1 antagonistic activity and no cardiotoxicity through virtual screening using two MCHR1 binding affinity prediction models and an hERG-induced cardiotoxicity prediction model. In addition, we explored other possibilities for expanding the new indications for KRX-104130 using a transcriptome-based drug repositioning approach. KRX-104130 increased the expression of low-density lipoprotein receptor (LDLR), which induced cholesterol reduction in the gene expression analysis. This was confirmed by comparison with gene expression in a nonalcoholic steatohepatitis (NASH) patient group. In a NASH mouse model, the administration of KRX-104130 showed a protective effect by reducing hepatic lipid accumulation, liver injury, and histopathological changes, indicating a promising prospect for the therapeutic effect of NASH as a new indication for MCHR1 antagonists.

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Synthesis and SAR study of pyrrolo[3,4-b]pyridin-7(6H)-one derivatives as melanin concentrating hormone receptor 1 (MCH-R1) antagonists

Cited by 9 publications

References 25 publications

Amino Acid Modified Xanthone Derivatives: Novel, Highly Promising Membrane-Active Antimicrobials for Multidrug-Resistant Gram-Positive Bacterial Infections

Amino Acid Modified Xanthone Derivatives: Novel, Highly Promising Membrane-Active Antimicrobials for Multidrug-Resistant Gram-Positive Bacterial Infections

Positional Analogue Scanning: An Effective Strategy for Multiparameter Optimization in Drug Design

Identification and New Indication of Melanin-Concentrating Hormone Receptor 1 (MCHR1) Antagonist Derived from Machine Learning and Transcriptome-Based Drug Repositioning Approaches

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