Discovery of Novel 5,5-Diarylpentadienamides as Orally Available Transient Receptor Potential Vanilloid 1 (TRPV1) Antagonists

Saku, Osamu; Ishida, Hiroshi; Atsumi, Eri; Sugimoto, Yohei; Kodaira, Hiroshi; Kato, Yasuki; Shirakura, Shiro; Nakasato, Yoshisuke

doi:10.1021/jm300101n

Cited by 52 publications

(30 citation statements)

References 27 publications

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“…Fuji Research Park has developed a chemical series of 5,5‐diphenylpentadienamides for targeting TRPV1 in vitro and in vivo . In this study, they investigated a variety of replacements for the 5‐position of dienamides with the goal of improving the related pharmacokinetics.…”

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

128

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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

128

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“…In a previous study, we discovered novel 5,5-diarylpentadienamides, including K-685, that act as orally active TRPV1 antagonists (26). We also evaluated the binding affinities of K-685 to 12 pain-related receptors and 7 ion channels other than TRPV1 and confirmed that K-685 had more than 1000-fold selectivity for TRPV1 over these receptors and channels (data not shown).…”

Section: Discussionmentioning

confidence: 57%

“…In a previous study, we discovered novel 5,5-diarylpentadienamides as orally active TRPV1 antagonists (26). These compounds inhibit the capsaicin-mediated Ca 2+ response through human and rat TRPV1 and reversed pain behaviors in a rat neuropathic pain model.…”

Section: +mentioning

confidence: 99%

K-685, a TRPV1 Antagonist, Blocks PKC-Sensitized TRPV1 Activation and Improves the Inflammatory Pain in a Rat Complete Freund’s Adjuvant Model

et al. 2013

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Abstract. Transient receptor potential vanilloid 1 (TRPV1) is a Ca 2+-permeable non-selective cation channel that transmits pain signals. TRPV1 is activated by multiple stimuli such as capsaicin, acid, and heat. During inflammation, TRPV1 is reported to be sensitized by protein kinase C (PKC) in dorsal root ganglia (DRG) neurons, which leads to reduction in the threshold of the temperature for TRPV1 activation to body temperature. This sensitization is considered to contribute to chronic inflammatory pain. In a previous study, we discovered orally active 5,5-diarylpentadienamide TRPV1 antagonists. To examine the effects of our TRPV1 antagonists on PKC-sensitized TRPV1, we developed an in vitro assay system to monitor the TRPV1 sensitization by PKC. In this assay system, our TRPV1 antagonists, such as (2E,4Z)-N-[(3R)-3-hydroxy-2-oxo-1,2,3,4-tetrahydro-5-quinolyl]-5-(4-isopropoxyphenyl)-5-(4-trifluoromethylphenyl)-2,4-pentadienamide (K-685), inhibited the activation of TRPV1 sensitized by PKC. The potentiation of heat-induced inward currents by PKC was seen in rat DRG neurons, and K-685 attenuated these currents. Furthermore, K-685 reversed the thermal hyperalgesia and mechanical allodynia in a rat complete Freund's adjuvant-induced inflammatory pain model. These results therefore suggest that K-685 has a strong potential as a new analgesic drug for the treatment of inflammatory pain.

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“…All of these amphiphiles were synthesized starting from glycerol which was first converted into 2‐hydroxypropane‐1,3‐diyl diacetate using vinyl acetate as the acylating reagent, by following the established bio‐catalytic procedure . The secondary hydroxyl group of 2‐hydroxypropane‐1,3‐diyl diacetate was then coupled with 4‐hydroxybenzoate via a Mitsunobu reaction . The resulting compound 9 was characterized from its spectral data.…”

Section: Resultsmentioning

confidence: 96%

Aggregation Behavior of Non‐ionic Twinned Amphiphiles and Their Application as Biomedical Nanocarriers

Singh

Thota

Schade

et al. 2017

Chemistry An Asian Journal

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A new class of twinned amphiphiles was developed by conjugating a pair of hydrophilic head groups from mPEG chains (M : 350 or 1000) and a pair of hydrophobic segments from linear alkyl chains (C or C ) through a novel spacer synthesized from glycerol and p-hydroxybenzoic acid. The aggregation phenomena of the amphiphiles were proven by DLS and fluorescence experiments, whereas size and morphology of the aggregates were evaluated by cryo-TEM. The measurements proved the formation of globular, thread-like or rod-like micelles as well as planar double-layer assemblies, depending on the amphiphile's molecular structure. The applicability of these non-ionic amphiphilic systems as nanocarriers for hydrophobic guest molecules was demonstrated by encapsulating a hydrophobic dye, Nile Red, and a hydrophobic drug, Nimodipine. The transport capacity results for both Nimodipine and Nile Red prove them as a promising candidate for drug delivery.

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Discovery of Novel 5,5-Diarylpentadienamides as Orally Available Transient Receptor Potential Vanilloid 1 (TRPV1) Antagonists

Cited by 52 publications

References 27 publications

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

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

K-685, a TRPV1 Antagonist, Blocks PKC-Sensitized TRPV1 Activation and Improves the Inflammatory Pain in a Rat Complete Freund’s Adjuvant Model

Aggregation Behavior of Non‐ionic Twinned Amphiphiles and Their Application as Biomedical Nanocarriers

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