Acipimox inhibits human carbonic anhydrases

Mori, Mattia; Supuran, Claudiu T.

doi:10.1080/14756366.2022.2037579

Cited by 10 publications

(10 citation statements)

References 55 publications

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“…However, they may provide interesting hints for the drug design of novel CA VA inhibitors belonging to new chemotypes compared to the well known sulphonamides, sulfamates or phenol derivatives. Acipimox 39 , a nicotinic acid derivative in clinical use for the treatment of hyperlipidaemia ( Figure 6 ) was also reported recently 65 to act as low micromolar hCA VA/VB inhibitor. By using computational methods, the same study suggested that acipimox coordinates through its carboxylate moiety to the zinc ion from the CA active site 65 .…”

Section: Drug Design Of Ca Inhibitors As Antiobesity Agentsmentioning

confidence: 57%

“…Acipimox 39 , a nicotinic acid derivative in clinical use for the treatment of hyperlipidaemia ( Figure 6 ) was also reported recently 65 to act as low micromolar hCA VA/VB inhibitor. By using computational methods, the same study suggested that acipimox coordinates through its carboxylate moiety to the zinc ion from the CA active site 65 .…”

Section: Drug Design Of Ca Inhibitors As Antiobesity Agentsmentioning

confidence: 57%

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Anti-obesity carbonic anhydrase inhibitors: challenges and opportunities

Supuran

2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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The mitochondrial isoforms VA/VB of metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) are involved in metabolic processes, such as de novo lipogenesis and fatty acid biosynthesis. We review the drug design landscape for obtaining CA VA/VB-selective/effective inhibitors, starting from the clinical observations that CA inhibitory drugs, such as the antiepileptics topiramate and zonisamide, or the diuretic acetazolamide induce a significant weight loss. The main approaches for designing such compounds consisted in drug repurposing of already known CA inhibitors (CAIs); screening of synthetic/natural products libraries both in the classical and virtual modes, and de novo drug design using the tail approach. A number of such studies allowed the identification of lead compounds diverse from sulphonamides, such as tropolones, phenols, polyphenols, flavones, glycosides, fludarabine, lenvatinib, rufinamide, etc., for which the binding mode to the enzyme is not always well understood. Classical drug design studies of sulphonamides, sulfamates and sulfamides afforded low nanomolar mitochondrial CA-selective inhibitors, but detailed antiobesity studies were poorly performed with most of them. A breakthrough in the field may be constituted by the design of hybrids incorporating CAIs and other antiobesity chemotypes.

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Section: Drug Design Of Ca Inhibitors As Antiobesity Agentsmentioning

confidence: 57%

Section: Drug Design Of Ca Inhibitors As Antiobesity Agentsmentioning

confidence: 57%

Anti-obesity carbonic anhydrase inhibitors: challenges and opportunities

Supuran

2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…It inhibits VLDL synthesis, and consequently lowers plasma triglyceride levels while elevating highdensity lipoprotein (HDL). 108 Carbadox and olaquindox (Figure 8) are structural analogues of the natural products iodinin and myxin. They have been used as antimicrobial agents in veterinary medicine as feed additives to promote growth.…”

Section: Drugs Containing N-oxide Groupsmentioning

confidence: 99%

“…This leads to a reduction in the precursor pool size of the very low-density lipoprotein (VLDL)-triglyceride. It inhibits VLDL synthesis, and consequently lowers plasma triglyceride levels while elevating high-density lipoprotein (HDL) …”

Section: Drugs Containing N-oxide Groupsmentioning

confidence: 99%

Medicinal Chemistry of Drugs with N-Oxide Functionalities

Kobus,

Friedrich,

Zorn

et al. 2024

J. Med. Chem.

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Molecules with N-oxide functionalities are omnipresent in nature and play an important role in Medicinal Chemistry. They are synthetic or biosynthetic intermediates, prodrugs, drugs, or polymers for applications in drug development and surface engineering. Typically, the N-oxide group is critical for biomedical applications of these molecules. It may provide water solubility or decrease membrane permeability or immunogenicity. In other cases, the N-oxide has a special redox reactivity which is important for drug targeting and/or cytotoxicity. Many of the underlying mechanisms have only recently been discovered, and the number of applications of N-oxides in the healthcare field is rapidly growing. This Perspective article gives a short summary of the properties of N-oxides and their synthesis. It also provides a discussion of current applications of N-oxides in the biomedical field and explains the basic molecular mechanisms responsible for their biological activity. ■ SIGNIFICANCE Relevance of N-oxides for Medicinal Chemistry:• N + −O − bonds are highly polar and form strong hydrogen bonds. They may be inert or reactive in biological systems depending on their substituents.• N-Oxide groups can be used to increase the solubility of drugs and decrease membrane permeability.• Many heteroaromatic and aniline-derived N-oxides are reduced enzymatically in vivo and find applications as hypoxia-activated prodrugs.• Polymeric N-oxides have excellent blood compatibility, are nonimmunogenic and are nonadhesive for microorganisms (stealth materials).

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“…The ubiquitous metalloenzymes carbonic anhydrases (CAs) [ 1 , 2 , 3 , 4 , 5 , 6 ] are present in bacteria [ 7 , 8 ] and fungi [ 9 , 10 , 11 , 12 ], plants and animals. Inhibitors of these enzymes have been clinically exploited for decades, and the discovery of multiple human isoforms [ 13 , 14 , 15 , 16 , 17 , 18 ] has led to many new applications and the development of new therapeutic principles, among them antiglaucoma [ 19 , 20 , 21 ] and antitumor drugs but also antiepileptic [ 22 , 23 , 24 , 25 , 26 ] and antiobesity drugs [ 27 , 28 , 29 ] as well as agents for the management of Alzheimer’s disease [ 30 , 31 ], neuropathic pain, cerebral ischemia, and some forms of arthritis [ 32 , 33 , 34 ]. Furthermore, the development of inhibitors for bacterial carbonic anhydrases is thought as a new concept to develop antibacterial drugs [ 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ].…”

Section: Introductionmentioning

confidence: 99%

Small Structural Differences Govern the Carbonic Anhydrase II Inhibition Activity of Cytotoxic Triterpene Acetazolamide Conjugates

et al. 2023

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Acetylated triterpenoids betulin, oleanolic acid, ursolic acid, and glycyrrhetinic acid were converted into their succinyl-spacered acetazolamide conjugates. These conjugates were screened for their inhibitory activity onto carbonic anhydrase II and their cytotoxicity employing several human tumor cell lines and non-malignant fibroblasts. As a result, the best inhibitors were derived from betulin and glycyrrhetinic acid while those derived from ursolic or oleanolic acid were significantly weaker inhibitors but also of diminished cytotoxicity. A betulin-derived conjugate held a Ki = 0.129 μM and an EC50 = 8.5 μM for human A375 melanoma cells.

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Acipimox inhibits human carbonic anhydrases

Cited by 10 publications

References 55 publications

Anti-obesity carbonic anhydrase inhibitors: challenges and opportunities

Anti-obesity carbonic anhydrase inhibitors: challenges and opportunities

Medicinal Chemistry of Drugs with N-Oxide Functionalities

Small Structural Differences Govern the Carbonic Anhydrase II Inhibition Activity of Cytotoxic Triterpene Acetazolamide Conjugates

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