Discovery of (<i>R</i>)-1-(7-Chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea (A-1165442): A Temperature-Neutral Transient Receptor Potential Vanilloid-1 (TRPV1) Antagonist with Analgesic Efficacy

Voight, Eric A.; Gomtsyan, Arthur; Daanen, Jerome F.; Perner, Richard J.; Schmidt, Robert George; Bayburt, Erol K.; DiDomenico, Stanley; McDonald, Heath A.; Puttfarcken, Pamela S.; Chen, Jun; Neelands, Torben R.; Bianchi, Bruce R.; Han, Ping; Reilly, Regina M.; Franklin, Pamela H.; Segreti, Jason A.; Nelson, Richard Alan; Su, Zhi; King, Andrew J.; Polakowski, James S.; Baker, Scott J.; Gauvin, Donna M.; Lewis, LaGeisha; Mikusa, Joseph P.; Joshi, Sunil Kumar; Faltynek, Connie R.; Kym, Philip R.; Kort, Michael E.

doi:10.1021/jm500916t

Cited by 38 publications

(33 citation statements)

References 53 publications

(89 reference statements)

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“…These data encouraged a more focused investigation of SAR to optimization of the chromanyl urea series, concluding in the discovery of R ‐1‐(7‐chloro‐2,2‐bis(fluoromethyl)chroman‐4‐yl)‐3‐(3‐methylisoquinolin‐5‐yl)‐urea 28 (A‐1165442; Fig. ), a TRPV1 antagonist with good analgesic effect, temperature‐neutral profile, favorable pharmacokinetic behavior, and significant efficacy against osteoarthritic pain in rodents (hTRPV1 IC 50 = 9 nM in Ca 2+ influx assay) …”

Section: Medicinal Chemistry Of Trpv1 Antagonistsmentioning

confidence: 99%

Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists

Tabrizi

Baraldi

et al. 2016

Medicinal Research Reviews

120

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Transient receptor potential vanilloid 1 (TRPV1) is an ion channel expressed on sensory neurons triggering an influx of cations. TRPV1 receptors function as homotetramers responsive to heat, proinflammatory substances, lipoxygenase products, resiniferatoxin, endocannabinoids, protons, and peptide toxins. Its phosphorylation increases sensitivity to both chemical and thermal stimuli, while desensitization involves a calcium-dependent mechanism resulting in receptor dephosphorylation. TRPV1 functions as a sensor of noxious stimuli and may represent a target to avoid pain and injury. TRPV1 activation has been associated to chronic inflammatory pain and peripheral neuropathy. Its expression is also detected in nonneuronal areas such as bladder, lungs, and cochlea where TRPV1 activation is responsible for pathology development of cystitis, asthma, and hearing loss. This review offers a comprehensive overview about TRPV1 receptor in the pathophysiology of chronic pain, epilepsy, cough, bladder disorders, diabetes, obesity, and hearing loss, highlighting how drug development targeting this channel could have a clinical therapeutic potential. Furthermore, it summarizes the advances of medicinal chemistry research leading to the identification of highly selective TRPV1 antagonists and their analysis of structure-activity relationships (SARs) focusing on new strategies to target this channel.

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Section: Medicinal Chemistry Of Trpv1 Antagonistsmentioning

confidence: 99%

Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists

Tabrizi

Baraldi

et al. 2016

Medicinal Research Reviews

120

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“…With a second generation of TRPV1 antagonists under development that demonstrate analgesic effects in the MIA model and are devoid of the on-target-mediated side effects of hyperthermia [77] and burn risk, the clinical evaluation of TRPV1 antagonists can now progress unhampered.…”

Section: Resultsmentioning

confidence: 99%

“…The blockade of heat or capsaicin activation of TRPV1 does not make a significant contribution, whereas the potency of TRPV1 antagonists to induce hyperthermia relates most closely to their potency to block proton-induced activation of TRPV1. This information has been exploited in the development of a second-generation TRPV1 antagonists without the side effects of burn risk and hyperthermia [76,77]. For instance, AMG8562 an antagonist that potentiates TRPV1 activation by protons through positive allosteric modulation does not cause hyperthermia in rodents [78]; however, there is a requirement for a 46-fold higher plasma concentration for comparable efficacy when compared with AM8163 a compound that blocks all modalities of activation [78].…”

Section: Adverse Effects Of Trpv1 Antagonismmentioning

confidence: 99%

TRPV1 antagonists in the treatment of osteoarthritis pain

Kelly¹

2015

International Journal of Clinical Rheumatology

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Pain is the dominant symptom of osteoarthritis (OA) and available analgesic treatments offer inadequate pain relief. The capsaicin receptor, TRPV1 is considered to be a promising analgesic target. TRPV1 is expressed in multiple cell types of the joint. A variant of the TRPV1 gene is associated with the risk of developing symptomatic OA and synovial TRPV1 expression is increased in OA patients undergoing total joint replacement. Potent and selective small molecule TRPV1 antagonists have analgesic effects in preclinical models of OA highlighting the potential utility of TRPV1 antagonists in OA pain management. However, use of these compounds is associated with serious on-target-mediated side effects and analgesic efficacy in OA patients in clinical trials remains to be proven. This review article will discuss recent findings in this area and explore the potential utility of TRPV1 antagonists in the treatment of OA pain. Targeting TRPV1 in the treatment of OA painThere is now a significant body of evidence supporting targeting TRPV1), for the treatment of OA pain [7][8][9][10]. The relevance of TRPV1 to OA pain was highlighted by a recent human genetic study that discovered polymorphisms in the TRPV1 gene associated with symptomatic knee OA [11]. Persistent activation of TRPV1 by the agonist capsaicin causes TRPV1 desensitization and inactivation of TRPV1 expressing sensory neurones. These effects account for why TRPV1 agonists can produce paradoxical analgesia. Topical capsaicin is more effective than placebo for a 50% reduction in pain with a number needed to treat of 8.1 [5]. However, the use of topical capsaicin is associated with increased local adverse events and withdrawals due to these events [12]. The TRPV1 agonist 4975 (Adlea™) developed by Anesiva has been shown to cause a reduction in pain scores with no safety concerns following a single intra-articular injection in end-stage OA patients [13]. A recent Phase II clinical trial demonstrated analgesic efficacy of topic administration of civamide (cis isomer of capsaicin) in patients with knee OA pain [14] and has been approved for topical treatment as a 0.075% cream for the relief of pain in OA patients [14]. Qutenza ® an 8% capsaicin patch is indicated for the management of neuropathic pain associated with postherpetic neuralgia. The long-term analgesic efficacy of topical capsaicin cream in the treatment of knee OA pain [12] and of a capsaicin patch in postherpatic neuralgia provides clear evidence that the blockade of TRPV1 expressing nociceptive afferents at the periphery is a useful strategy to treat chronic pain, although this does not necessarily inform us of the role of TRPV1 itself. The relatively low effectiveness of capsaicin cream and the need to reapply, along with the associated skin irritation has limited civamides' use. Despite this, TRPV1 remains a potential target for OA pain treatment with accumulating preclinical data suggesting that TRPV1 has an important role in the maintenance of established OA pain [7][8][9][10]15]. Several pharma...

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“…Fortunately, several compounds have been found that differentially affect the channel. For instance, some block capsaicin, but not heat activation, suggesting that it could be feasible to separate the analgesic effects of TRPV1 antagonists from harmful side effects (Lehto and others 2008) Indeed, second generation antagonists such as AMG8562, APHC1, APHC3 and A-1165442, 52 have already been tested for several inflammatory conditions with success in pain reduction while avoiding hyperthermia (Lehto and others 2008; Reilly and others 2012; Andreev and others 2013; Voight and others 2014). …”

Section: Trpv1mentioning

confidence: 99%

ThermoTRPs and Pain

Laing

Dhaka

2015

Neuroscientist

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The ability of the body to perceive noxious stimuli lies in a heterogeneous group of primary somatosensory neurons termed nociceptors. The molecular receptors of noxious mechanical, temperature or chemical stimuli are expressed in these neurons and have drawn considerable attention as possible targets for analgesic development to improve treatment for the millions who suffer from chronic pain conditions. A number of thermoTRPs, a subset of the transient receptor potential family of ion channels, are activated by a wide range on noxious stimuli. In this review, we review the function of these channels and examine the evidence that thermoTRPs play a vital role in acute, inflammatory and neuropathic nociception.

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Discovery of (R)-1-(7-Chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea (A-1165442): A Temperature-Neutral Transient Receptor Potential Vanilloid-1 (TRPV1) Antagonist with Analgesic Efficacy

Cited by 38 publications

References 53 publications

Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists

Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists

TRPV1 antagonists in the treatment of osteoarthritis pain

ThermoTRPs and Pain

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