Scaffold Morphing Identifies 3-Pyridyl Azetidine Ureas as Inhibitors of Nicotinamide Phosphoribosyltransferase (NAMPT)

Palacios, Daniel S.; Meredith, Erik; Kawanami, Toshio; Adams, Christopher M.; Chen, Xin; Darsigny, Veronique; Palermo, Mark; Baird, Daniel; George, Elizabeth; Guy, Chantale T.; Hewett, Jeffrey; Tierney, Laryssa; Thigale, Sachin; Wang, Louis; Weihofen, W.A.

doi:10.1021/acsmedchemlett.9b00325

Cited by 15 publications

(20 citation statements)

References 15 publications

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“…The most recent structural iteration of this chemotype focused on identifying additional structural elements capable of projecting the pyridine nitrogen atom with the same trajectory as 73a and 73d, with an azetidine ring fulfilling the requirements based on a modeling overlay of 73f with the cocrystal structures of the two prototype inhibitors. 150 Evaluation of 73f revealed it to be a potent NAMPT inhibitor that translated into potent inhibition of A2780 cell proliferation, fully confirming the modeling predictions. A further increase in cell-based potency was realized with the isoindolone homologue 73g, which provided a platform to demonstrate the uniqueness of the azetidine ring, since both enantiomers of the pyrrolidine analogues 73h and the piperidine 73i were poorly active in the cell viability assay (Figure 24C).…”

Section: Bioisosteric Replacement Ofsupporting

confidence: 57%

“…While 73d binds to and inhibits the enzyme in a biochemical assay, cellular activity appears to be a function of ribophosphorylation of the pyridine nitrogen atom, which produces a conjugated inhibitor that is more potent, acting as a nicotinamide mimic, a process that would be expected to be sensitive to the presentation of the azine heteroatom to the enzyme. The most recent structural iteration of this chemotype focused on identifying additional structural elements capable of projecting the pyridine nitrogen atom with the same trajectory as 73a and 73d , with an azetidine ring fulfilling the requirements based on a modeling overlay of 73f with the cocrystal structures of the two prototype inhibitors . Evaluation of 73f revealed it to be a potent NAMPT inhibitor that translated into potent inhibition of A2780 cell proliferation, fully confirming the modeling predictions.…”

Section: Bioisosteric Replacement Of Meta-substituted Phenyl Ringsmentioning

confidence: 99%

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Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

2021

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The benzene moiety is the most prevalent ring system in marketed drugs, underscoring its historic popularity in drug design either as a pharmacophore or as a scaffold that projects pharmacophoric elements. However, introspective analyses of medicinal chemistry practices at the beginning of the 21st century highlighted the indiscriminate deployment of phenyl rings as an important contributor to the poor physicochemical properties of advanced molecules, which limited their prospects of being developed into effective drugs. This Perspective deliberates on the design and applications of bioisosteric replacements for a phenyl ring that have provided practical solutions to a range of developability problems frequently encountered in lead optimization campaigns. While the effect of phenyl ring replacements on compound properties is contextual in nature, bioisosteric substitution can lead to enhanced potency, solubility, and metabolic stability while reducing lipophilicity, plasma protein binding, phospholipidosis potential, and inhibition of cytochrome P450 enzymes and the hERG channel.

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Section: Bioisosteric Replacement Ofsupporting

confidence: 57%

Section: Bioisosteric Replacement Of Meta-substituted Phenyl Ringsmentioning

confidence: 99%

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

2021

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“…In this study, the adsorption and desorption behaviors at the urea–HA-Np interface of morphologically different HA-Np thin films are studied. Ureas have been used in medicinal chemistry for the design and optimization of various therapeutic agents. − They are also used in the field of agriculture as a nitrogen source for the plants. ,, Furthermore, urea has become an important functional group in biomolecules with a broad range of bioactivities due to its unique hydrogen bonding capabilities. In this study, urea is used as a model molecule with the view of developing a broader understanding of interactions of urea-based biomolecules.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Insights into Interactions at Urea–Hydroxyapatite Nanoparticle Interface

et al. 2021

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Development of controlled release biomolecules by surface modification of hydroxyapatite nanoparticles has recently gained popularity in the areas of bionanotechnology and nanomedicine. However, optimization of these biomolecules for applications such as drug delivery, nutrient delivery requires a systematic understanding of binding mechanisms and interfacial kinetics at the molecular level between the nanomatrix and the active compound. In this research, urea is used as a model molecule to investigate its interactions with two morphologically different thin films of hydroxyapatite nanoparticles. These thin films were fabricated on quartz crystal piezoelectric sensors to selectively expose Ca 2+ and PO 4 3− sites of hydroxyapatite. Respective urea adsorption and desorption on both of these sites were monitored in situ and in real time in the phosphate buffer solution that mimics body fluids. The measured kinetic parameters, which corroborate structural predisposition for controlled release, show desorption rates that are one-tenth of the adsorption rates on both surfaces. Furthermore, the rate of desorption from the PO 4 3− site is one-half the rate of desorption from the Ca 2+ site. The Hill kinetic model was found to satisfactorily fit data, which explains cooperative binding between the hydroxyapatite nanoparticle thin film and urea. Fourier transform infrared spectra and X-ray photoemission spectra of the urea adsorbed on the above surfaces confirm the cooperative binding. It also elucidates the different binding mechanisms between urea and hydroxyapatite that contribute to the changes in the interfacial kinetics. These findings provide valuable information for structurally optimizing hydroxyapatite nanoparticle surfaces to control interfacial kinetics for applications in bionanotechnology and nanomedicine.

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“…This compound could be useful in tumours in which sirtuins act as oncogenes. Nampt-IN-5 is a NAMPT inhibitor that also acts on CYP3A4 activity, enhancing its cytotoxic effect both in vitro and in xenograft models [ 149 ]. In addition, new NAMPT inhibitors have been conjugated with antibodies, which are called ADCs (antibody–drug conjugates), with the aim of specifically targeting the drug to the tumour while avoiding damage to healthy tissues.…”

Section: Nampt As a Therapeutic Strategymentioning

confidence: 99%

Nicotinamide Adenine Dinucleotide (NAD) Metabolism as a Relevant Target in Cancer

Carnero

2022

Cells

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NAD+ is an important metabolite in cell homeostasis that acts as an essential cofactor in oxidation–reduction (redox) reactions in various energy production processes, such as the Krebs cycle, fatty acid oxidation, glycolysis and serine biosynthesis. Furthermore, high NAD+ levels are required since they also participate in many other nonredox molecular processes, such as DNA repair, posttranslational modifications, cell signalling, senescence, inflammatory responses and apoptosis. In these nonredox reactions, NAD+ is an ADP-ribose donor for enzymes such as sirtuins (SIRTs), poly-(ADP-ribose) polymerases (PARPs) and cyclic ADP-ribose (cADPRs). Therefore, to meet both redox and nonredox NAD+ demands, tumour cells must maintain high NAD+ levels, enhancing their synthesis mainly through the salvage pathway. NAMPT, the rate-limiting enzyme of this pathway, has been identified as an oncogene in some cancer types. Thus, NAMPT has been proposed as a suitable target for cancer therapy. NAMPT inhibition causes the depletion of NAD+ content in the cell, leading to the inhibition of ATP synthesis. This effect can cause a decrease in tumour cell proliferation and cell death, mainly by apoptosis. Therefore, in recent years, many specific inhibitors of NAMPT have been developed, and some of them are currently in clinical trials. Here we review the NAD metabolism as a cancer therapy target.

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Scaffold Morphing Identifies 3-Pyridyl Azetidine Ureas as Inhibitors of Nicotinamide Phosphoribosyltransferase (NAMPT)

Cited by 15 publications

References 15 publications

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

Mechanistic Insights into Interactions at Urea–Hydroxyapatite Nanoparticle Interface

Nicotinamide Adenine Dinucleotide (NAD) Metabolism as a Relevant Target in Cancer

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