Discovery and optimization of aminopyrimidinones as potent and state-dependent Nav1.7 antagonists

Nguyen, Hanh Nho; Bregman, Howie; Buchanan, Joan L.; Du, Bingfan; Feric, Elma; Huang, Liyue; Li, Xingwen; Ligutti, Joseph; Liu, Dong; Malmberg, Annika B.; Matson, David J.; McDermott, Jeff S.; Patel, Vinod F.; Wilenkin, Ben; Zou, Anruo; McDonough, Stefan I.; DiMauro, Erin F.

doi:10.1016/j.bmcl.2011.11.111

Cited by 12 publications

(12 citation statements)

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“…[238,[241][242][243][244][245][246][247][248] The nanomolar-potent A-803467 displayed > 100-fold selectivity versus human Na v 1.2, Na v 1.3, Na v 1.5, and Na v 1.7 as well as in vivo antinociception in animal models of neuropathic and inflammatory pain. [255,258] Remarkably, the binding site for one Amgen compound has been demonstrated to differ from the local anesthetic binding site. [251] A backup program aimed at the modification of the furane nucleus of A-803467 to afford improved aqueous solubility and oral bioavailability has also been reported.…”

Section: Individual Subtypes As Drug Targetsmentioning

confidence: 99%

“…Xenon Pharmaceuticals reported two candidates in clinical development which, according to the company's website, "specifically target the sodium channels such as Na v 1.7", even though selectivity data for Na v 1.7 over other subtypes have not been yet released in the public domain. Aminopyrazines 2012 Na v 1.7 - [257] Aminopyrimidinones 2012 Na v 1.7 - [258] Aminotriazines 2011 Na v 1.7 Formalin model of pain (rats) [255] XEN907, spirooxindole 2011 Na v 1.7 - [362] Phenylisoxazoles 2011 Na v 1.7 - [363] Z123212 2011 Common strategy to identify voltage protocols for use-and statedependency assays in manual or automated whole-cell patch-clamp electrophysiology for any member of the Na v 1 channel family.…”

Section: Individual Subtypes As Drug Targetsmentioning

confidence: 99%

“…[252,253] These represent examples of pioneer isoform-selective smallmolecule agents, which are now accompanied by several other and more recent publications, including chemical matters from Abbott/Icagen (Na v 1.8) [254] and Amgen (Na v 1.7). [255,258] Remarkably, the binding site for one Amgen compound has been demonstrated to differ from the local anesthetic binding site. [255] The marketed secretolytic agent Ambroxol (Table 4), used in the treatment of respiratory diseases, has also been reported to preferentially block Na v 1.8 in a use-dependent manner and to be antinociceptive.…”

Section: Individual Subtypes As Drug Targetsmentioning

confidence: 99%

“…Note that the holding potential (usually between À120 and À80 mV) and test pulse duration (usually between 5 and 40 ms) dramatically influence the inactivation and recovery properties of Na v 1 channels, and therefore should be kept at a constant value for all outlined steps and final assay voltage protocols. Examples for the use of such voltage protocols for the in vitro pharmacological characterization of compounds are given in Figures 2 and 4 Aminopyrazines 2012 Na v 1.7 - [257] Aminopyrimidinones 2012 Na v 1.7 - [258] Aminotriazines 2011 Na v 1.7 Formalin model of pain (rats) [255] XEN907, spirooxindole 2011 Na v 1.7 - [362] Phenylisoxazoles 2011 Na v 1.7 - [363] Z123212 2011…”

Section: Individual Subtypes As Drug Targetsmentioning

confidence: 99%

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Advances in Targeting Voltage‐Gated Sodium Channels with Small Molecules

Nardi¹,

Damann²,

Hertrampf³

et al. 2012

ChemMedChem

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Blockade of voltage-gated sodium channels (VGSCs) has been used successfully in the clinic to enable control of pathological firing patterns that occur in conditions as diverse as chronic pain, epilepsy, and arrhythmias. Herein we review the state of the art in marketed sodium channel inhibitors, including a brief compendium of their binding sites and of the cellular and molecular biology of sodium channels. Despite the preferential action of this drug class toward over-excited cells, which significantly limits potential undesired side effects on other cells, the need to develop a second generation of sodium channel inhibitors to overcome their critical clinical shortcomings is apparent. Current approaches in drug discovery to deliver novel and truly innovative sodium channel inhibitors is next presented by surveying the most recent medicinal chemistry breakthroughs in the field of small molecules and developments in automated patch-clamp platforms. Various strategies aimed at identifying small molecules that target either particular isoforms of sodium channels involved in specific diseases or anomalous sodium channel currents, irrespective of the isoform by which they have been generated, are critically discussed and revised.

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Section: Individual Subtypes As Drug Targetsmentioning

confidence: 99%

Section: Individual Subtypes As Drug Targetsmentioning

confidence: 99%

Section: Individual Subtypes As Drug Targetsmentioning

confidence: 99%

Section: Individual Subtypes As Drug Targetsmentioning

confidence: 99%

See 2 more Smart Citations

Advances in Targeting Voltage‐Gated Sodium Channels with Small Molecules

Nardi¹,

Damann²,

Hertrampf³

et al. 2012

ChemMedChem

View full text Add to dashboard Cite

show abstract

“…An extremely rare pain phenotype characterized by a total absence of pain perception (“congenital insensitivity to pain”) with no associated neuropathy has been associated with the mutations in the gene SCN9A , encoding the α-subunit of the voltage-gated sodium channel NaV1.7 17,18. This discovery has already opened directions for novel generations of therapeutic agents blocking NaV1.7,19,20 with the hope that these drugs may provide selective and safe analgesia/anesthesia. Another clinical phenotype resulting from loss-of-function mutations of NaV1.7 termed “congenital indifference to pain,” refers to individuals who actually recognize painful stimuli but lack the affective-motivational component of pain perception, do not show withdrawal responses, and often die in childhood 21.…”

Section: Interindividual Variability In Pain Sensitivitymentioning

confidence: 99%

Pharmacogenomic considerations in opioid analgesia

Vuilleumier

Stamer

Landau

2012

PGPM

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Translating pharmacogenetics to clinical practice has been particularly challenging in the context of pain, due to the complexity of this multifaceted phenotype and the overall subjective nature of pain perception and response to analgesia. Overall, numerous genes involved with the pharmacokinetics and dynamics of opioids response are candidate genes in the context of opioid analgesia. The clinical relevance of CYP2D6 genotyping to predict analgesic outcomes is still relatively unknown; the two extremes in CYP2D6 genotype (ultrarapid and poor metabolism) seem to predict pain response and/or adverse effects. Overall, the level of evidence linking genetic variability (CYP2D6 and CYP3A4) to oxycodone response and phenotype (altered biotransformation of oxycodone into oxymorphone and overall clearance of oxycodone and oxymorphone) is strong; however, there has been no randomized clinical trial on the benefits of genetic testing prior to oxycodone therapy. On the other hand, predicting the analgesic response to morphine based on pharmacogenetic testing is more complex; though there was hope that simple genetic testing would allow tailoring morphine doses to provide optimal analgesia, this is unlikely to occur. A variety of polymorphisms clearly influence pain perception and behavior in response to pain. However, the response to analgesics also differs depending on the pain modality and the potential for repeated noxious stimuli, the opioid prescribed, and even its route of administration.

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