| Candidate ID: | R0155 |
| Source ID: | DB00461 |
| Source Type: | approved |
| Compound Type: |
small molecule
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| Compound Name: |
Nabumetone
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| Synonyms: |
4-(6-Methoxy-2-naphthalenyl)-2-butanone; 4-(6-Methoxy-2-naphthyl)-2-butanone; Nabumetone
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| Molecular Formula: |
C15H16O2
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| SMILES: |
COC1=CC2=C(C=C1)C=C(CCC(C)=O)C=C2
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| Structure: |
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| DrugBank Description: |
Nabumetone was originally developed as a non-acidic non-steroidal anti-inflammatory drug (NSAID). It was thought to avoid trapping of the drug in the stomach by making it unable to dissociate into ions which was believed to reduce GI toxicity by limiting local action. While slightly reduced, possibly due to a degree of cyclooxygenase-2 selectivity (COX-2), nabumetone still produces significant adverse effects in the GI tract. The molecule itself is a pro-drug with its 6-methoxy-2-naphthylacetic acid (6-MNA) metabolite acting as a potent COX inhibitor similar in structure to . Nabumetone was developed by Smithkline Beecham under the trade name Relafen and first received FDA approval in December, 1991.
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| CAS Number: |
42924-53-8
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| Molecular Weight: |
228.2863
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| DrugBank Indication: |
**Indicated** for:
1) Symptomatic relief in rheumatoid arthritis.
2) Symptomatic relief in osteoarthritis.
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| DrugBank Pharmacology: |
NSAIDs, like nabumetone, are well established as analgesics. NSAIDs reduce both peripheral and central sensitization of nociceptive neurons due to inflammation which contribute to hyperalgesia and allodynia. This sensitization occurs through reducing the action potential threshold in peripheral neurons, reducing the intensity of painful stimuli needed to produce a painful sensation. Centrally, activation of dorsal horn neurons occurs along with increased release of glutamate, calcitonin gene-related peptide (CGRP), and substance P which increase the transmission of painful stimuli. Coupled with this is an inhibition glycinergic neurons which normally inhibit pain transmission, a phenomenon known as disinhibition. Increased activity ofn-methyl d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors leads to the establishment of central sensitization, allowing both mild painful and innocuous stimuli to produce action potentials in nociceptive projection neurons. NSAIDs are effective in reducing mild-moderate acute and chronic nociceptive pain, however, the usefulness of NSAIDs in neuropathic pain is limited.
The anti-inflammatory effect of NSAIDs is mediated by preventing vasodilation, increases in vascular permeability, and the release of cytokines from endothelial cells. These three effects together prevent immunocompetent cells from migrating to the site of injury thereby preventing additional damage and inflammation due to activation of the immune system at the site of damage. PGs also modulate T-helper cell activation and differentiation, an activity which is thought to be of importance in arthritic conditions.
The anti-pyretic effect of NSAIDs is mediated through preventing increases in temperature by prostaglandins (PGs) via the hypothalamus. Activation of this process by other inflammatory mediators relies upon subsequent action by PGs, therefore NSAIDs are able to reduce fever due to these mediators as well.
The adverse effects of NSAIDs are related to their therapeutic effects. The same vasodilatory action which occurs in inflammation also serves to regulate blood flow to the kidneys through the afferent renal arteries. NSAIDs are widely known as nephrotoxic agents as the reduction in PGs produces vasoconstriction of these arteries resulting in reduced blood flow to the kidneys and a subsequent decline in renal function. Reductions in mucus and HCO<sub>3</sub><sup>-</sup> secretion in the stomach increases the risk of ulceration by limiting the protection mediated by PGs. Lastly, COX-2 selective agents like nabumetone can unbalance prothrombotic and antithrombotic prostanoid generation leading to increased platelet aggregation and increased risk of thrombosis.
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| DrugBank MoA: |
Nabumetone's active metabolite, 6-MNA, is an inhibitor of both COX-1 and COX-2 although it exhibits some COX-2 selectivity. Inhibition of COX-1 and COX-2 reduces conversion of arachidonic acid to PGs and thromboxane (TXA<sub>2</sub>). This reduction in prostanoid production is the common mechanism that mediates the effects of nambutone.
PGE<sub>2</sub> is the primary PG involved in modulation of nociception. It mediates peripheral sensitization through a variety of effects. PGE<sub>2</sub> activates the G<sub>q</sub>-coupled EP<sub>1</sub> receptor leading to increased activity of the inositol trisphosphate/phospholipase C pathway. Activation of this pathway releases intracellular stores of calcium which directly reduces action potential threshold and activates protein kinase C (PKC) which contributes to several indirect mechanisms. PGE<sub>2</sub> also activates the EP<sub>4</sub> receptor, coupled to G<sub>s</sub>, which activates the adenylyl cyclase/protein kinase A (AC/PKA) signaling pathway. PKA and PKC both contribute to the potentiation of transient receptor potential cation channel subfamily V member 1 (TRPV1) potentiation, which increases sensitivity to heat stimuli. They also activate tetrodotoxin-resistant sodium channels and inhibit inward potassium currents. PKA further contributes to the activation of the P2X3 purine receptor and sensitization of T-type calcium channels. The activation and sensitization of depolarizing ion channels and inhibition of inward potassium currents serve to reduce the intensity of stimulus necessary to generate action potentials in nociceptive sensory afferents. PGE<sub>2</sub> act via EP<sub>3</sub> to increase sensitivity to bradykinin and via EP<sub>2</sub> to further increase heat sensitivity. Central sensitization occurs in the dorsal horn of the spinal cord and is mediated by the EP<sub>2</sub> receptor which couples to G<sub>s</sub>. Pre-synaptically, this receptor increases the release of pro-nociceptive neurotransmitters glutamate, CGRP, and substance P. Post-synaptically it increases the activity of AMPA and NMDA receptors and produces inhibition of inhibitory glycinergic neurons. Together these lead to a reduced threshold of activating, allowing low intensity stimuli to generate pain signals. PGI<sub>2</sub> is known to play a role via its G<sub>s</sub>-coupled IP receptor although the magnitude of its contribution varies. It has been proposed to be of greater importance in painful inflammatory conditions such as arthritis. By limiting sensitization, both peripheral and central, via these pathways NSAIDs can effectively reduce inflammatory pain.
PGI<sub>2</sub> and PGE<sub>2</sub> contribute to acute inflammation via their IP and EP<sub>2</sub> receptors. Similarly to β adrenergic receptors these are G<sub>s</sub>-coupled and mediate vasodilation through the AC/PKA pathway. PGE<sub>2</sub> also contributes by increasing leukocyte adhesion to the endothelium and attracts the cells to the site of injury. PGD<sub>2</sub> plays a role in the activation of endothelial cell release of cytokines through its DP<sub>1</sub> receptor. PGI<sub>2</sub> and PGE<sub>2</sub> modulate T-helper cell activation and differentiation through IP, EP<sub>2</sub>, and EP<sub>4</sub> receptors which is believed to be an important activity in the pathology of arthritic conditions. By limiting the production of these PGs at the site of injury, NSAIDs can reduce inflammation.
PGE<sub>2</sub> can cross the blood-brain barrier and act on excitatory G<sub>q</sub> EP<sub>3</sub> receptors on thermoregulatory neurons in the hypothalamus. This activation triggers an increase in heat-generation and a reduction in heat-loss to produce a fever. NSAIDs prevent the generation of PGE<sub>2</sub> thereby reducing the activity of these neurons.
The adverse effects of NSAIDs stem from the protective and regulatory roles of prostanoids which have been well-characterized. PGI<sub>2</sub> and PGE<sub>2</sub> regulate blood flow to the kidney by similar mechanisms to the vasodilation they produce in inflammation. Prevention of this regulation by NSAIDs produces vasoconstriction which limits renal function by reducing blood flow and the hydrostatic pressure which drives filtration. PGE<sub>2</sub> also regulates gastric protection via EP<sub>3</sub> receptors which are, in this location, coupled to G<sub>i</sub> which inhibits the AC/PKA pathway. This reduces the secretion of protons by H<sup>+</sup>/K<sup>+</sup> ATPase in parietal cells and increases the secretion of mucus and HCO<sub>3</sub><sup>-</sup> by superficial endothelial cells. Disruption of this protective action by NSAIDs lead to ulceration of the gastric mucosa. Lastly, disruption of PGI<sub>2</sub>, which opposes platelet aggregation, generation by COX-2 selective agents leads to an imbalance with TXA<sub>2</sub> generated by COX-1, which promotes aggregation of platelets, leading to increased risk of thrombosis. Since nabumetone is somewhat COX-2 selective it is thought to promote this imbalance and increase thrombotic risk.
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| Targets: |
Prostaglandin G/H synthase 2 inhibitor; Prostaglandin G/H synthase 1 inhibitor
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| Inclusion Criteria: |
Therapeutic strategy associated
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