2-Aminoalkyl nicotinamide derivatives as pure inverse agonists of the ghrelin receptor

Takahashi, Bitoku; Funami, Hideaki; Iwaki, Takehiko; Maruoka, Hiroshi; Nagahira, Asako; Koyama, Makoto; Kamiide, Yoshiyuki; Matsuo, Tsuyoshi; Muto, Tsuyoshi; Annoura, Hirokazu

doi:10.1016/j.bmcl.2015.04.040

Cited by 5 publications

(3 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…New potent GHS-R1a inverse agonists bearing the 2-aminoalkyl nicotinamide scaffold were identified by Asubio Pharma. 76 Optimization of the 2-aminoalkyl and 5-( N -propyl)pyrazolyl groups of the hit compound 38 (IC 50 (affinity) = 84 nM) afforded the lead 39 (IC 50 (affinity) = 0.96 nM) ( Figure 11 B), characterized by an azabicyclo ring at the 5-position and by a (2,3-(dihydrobenzofuran)methylamine at the 2-position of the pyridine ring. It peripherally blocked ghrelin-induced food intake and showed anorexigenic effects in mice.…”

Section: Medicinal Chemistry Of Ghs-r1a Ligandsmentioning

confidence: 99%

Advances in the Development of Nonpeptide Small Molecules Targeting Ghrelin Receptor

et al. 2022

View full text Add to dashboard Cite

Ghrelin is an octanoylated peptide acting by the activation of the growth hormone secretagogue receptor, namely, GHS-R1a. The involvement of ghrelin in several physiological processes, including stimulation of food intake, gastric emptying, body energy balance, glucose homeostasis, reduction of insulin secretion, and lipogenesis validates the considerable interest in GHS-R1a as a promising target for the treatment of numerous disorders. Over the years, several GHS-R1a ligands have been identified and some of them have been extensively studied in clinical trials. The recently resolved structures of GHS-R1a bound to ghrelin or potent ligands have provided useful information for the design of new GHS-R1a drugs. This perspective is focused on the development of recent nonpeptide small molecules acting as GHS-R1a agonists, antagonists, and inverse agonists, bearing classical or new molecular scaffolds, as well as on radiolabeled GHS-R1a ligands developed for imaging. Moreover, the pharmacological effects of the most studied ligands have been discussed.

show abstract

Section: Medicinal Chemistry Of Ghs-r1a Ligandsmentioning

confidence: 99%

Advances in the Development of Nonpeptide Small Molecules Targeting Ghrelin Receptor

et al. 2022

View full text Add to dashboard Cite

show abstract

“…LLE: Refers to a parameter used in the conception of drugs that permits evaluating the potential energy of a chemical bond and its lipophilicity to deduce its drug-likeness [18]. For the Ligand-receptor interaction to be favorable, the LLE value should be greater than or equal to 5 [19]. The corresponding mathematical equation is given by:…”

Section: B Affinity Studymentioning

confidence: 99%

In-silico Study of the Developed Hydroxychloroquine-based ACE2 Inhibitor Molecules Against COVID-19: Molecular Modeling and Docking

Zaher

Masango

Sobhi

et al. 2021

Eng. Technol. Appl. Sci. Res.

View full text Add to dashboard Cite

In the present study, we will verify the action of hydroxychloroquine-based derivatives on ACE2 which is considered to be the main portal of entry of the SARS-CoV-2 virus and constitutes an exciting target given its relative genetic stability compared to viral proteins. Thus, 81 molecules derived from hydroxychloroquine by substitutions at 4 different positions were generated in-silico and then studied for their affinity for ACE2 by molecular docking. Only 4 molecules were retained because of their affinity and bioavailability demonstrated by molecular dynamics and molecular docking calculations using COSMOtherm and Materials Studio software.

show abstract

“…6) Our program aimed to obtain a potent inverse agonist using highthroughput screening and subsequent structural optimization. 7) These efforts led to compound 1, which has a binding affinity of <1 nM and shows an anti-obesity effect in a rat model. 8) In this report, we present further optimization of this compound to improve lipophilicity and to avoid mechanism-based inactivation of CYP3A4.…”

mentioning

confidence: 99%

Structural Optimization of Ghrelin Receptor Inverse Agonists to Improve Lipophilicity and Avoid Mechanism-Based CYP3A4 Inactivation

Takahashi¹,

Funami²,

Shibata³

et al. 2015

CHEMICAL & PHARMACEUTICAL BULLETIN

Self Cite

View full text Add to dashboard Cite

Structural optimization of 2-aminonicotinamide derivatives as ghrelin receptor inverse agonists is reported. So as to avoid mechanism-based inactivation (MBI) of CYP3A4, 1,3-benzodioxol ring of the lead compound was modified. Improvement of the main activity and lipophilicity was achieved simultaneously, leading to compound 18a, which showed high lipophilic ligand efficiency (LLE) and low MBI activity.

show abstract

2-Aminoalkyl nicotinamide derivatives as pure inverse agonists of the ghrelin receptor

Cited by 5 publications

References 27 publications

Advances in the Development of Nonpeptide Small Molecules Targeting Ghrelin Receptor

Advances in the Development of Nonpeptide Small Molecules Targeting Ghrelin Receptor

In-silico Study of the Developed Hydroxychloroquine-based ACE2 Inhibitor Molecules Against COVID-19: Molecular Modeling and Docking

Structural Optimization of Ghrelin Receptor Inverse Agonists to Improve Lipophilicity and Avoid Mechanism-Based CYP3A4 Inactivation

Contact Info

Product

Resources

About