Discovery and lead optimisation of a potent, selective and orally bioavailable RARβ agonist for the potential treatment of nerve injury

Goncalves, Maria B.; Clarke, Earl E.; Jarvis, Christopher; Kalindjian, S. Barret; Pitcher, Thomas; Grist, John; Hobbs, Carl; Carlstedt, Thomas; Jack, J. J. B.; Brown, Jane T.; Mills, Mark; Mumford, Peter; Borthwick, Alan D.; Corcoran, Jonathan

doi:10.1016/j.bmcl.2019.02.011

Cited by 6 publications

(16 citation statements)

References 9 publications

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“…With this selective Beta precedent in mind, the replacement of the amide linkage in 7 with a variety of 5-membered heterocycles ( Table 6 ) was investigated. 12 …”

Section: Rarβ Agonistsmentioning

confidence: 99%

“…Also substitutions in the benzoic acid ring of 24 to give the 2-methyl, 3-methyl, 2-fluoro or 3-fluoro derivatives resulted in a loss of potency or RARβ selectivity when compared to 24 . 12 …”

Section: Rarβ Agonistsmentioning

confidence: 99%

“…Also 24 had a similar RARβ potency (EC 50 = 2.05 nM) and selectivity for RARβ over RARα (23 fold) and RARγ (5 fold) against the human RAR ligand-binding domains in a luciferase transactivation assay. 12 …”

Section: Rarβ Agonistsmentioning

confidence: 99%

“…The no adverse effect level (NOEL) in rat was found to be 1 mg/kg and this was due to defects in bone plate closure as these grow continuously in rats, whereas in Beagle the NOEL was higher at 3 mg/kg as the bone plates are not affected in adult dogs. 12 These doses have been shown to effective in stimulating axonal outgrowth in nerve injured rats. 12 …”

Section: Rarβ Agonistsmentioning

confidence: 99%

“…, 8 have been designed and prepared, these have generally been lipophilic acids without good drug-like properties and with low oral bioavailability. Recently this has been changing and drug design approaches to highly potent and selective RARα 9 and RARβ agonists 10 , 11 , 12 , with low lipophilicity that are orally bioavailable and less toxic have been developed that have a range of potential therapeutic uses. This review covers these new advances.…”

Section: Introductionmentioning

confidence: 99%

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Recent advances in the design of RAR α and RAR β agonists as orally bioavailable drugs. A review

Borthwick¹,

Goncalves

Corcoran

2020

Bioorganic & Medicinal Chemistry

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“…With this selective Beta precedent in mind, the replacement of the amide linkage in 7 with a variety of 5-membered heterocycles ( Table 6 ) was investigated. 12 …”

Section: Rarβ Agonistsmentioning

confidence: 99%

Section: Rarβ Agonistsmentioning

confidence: 99%

Section: Rarβ Agonistsmentioning

confidence: 99%

Section: Rarβ Agonistsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Recent advances in the design of RAR α and RAR β agonists as orally bioavailable drugs. A review

Borthwick¹,

Goncalves

Corcoran

2020

Bioorganic & Medicinal Chemistry

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RARβ Agonist Drug (C286) Demonstrates Efficacy in a Pre-clinical Neuropathic Pain Model Restoring Multiple Pathways via DNA Repair Mechanisms

et al. 2019

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SummaryNeuropathic pain (NP) is associated with profound gene expression alterations within the nociceptive system. DNA mechanisms, such as epigenetic remodeling and repair pathways have been implicated in NP. Here we have used a rat model of peripheral nerve injury to study the effect of a recently developed RARβ agonist, C286, currently under clinical research, in NP. A 4-week treatment initiated 2 days after the injury normalized pain sensation. Genome-wide and pathway enrichment analysis showed that multiple mechanisms persistently altered in the spinal cord were restored to preinjury levels by the agonist. Concomitant upregulation of DNA repair proteins, ATM and BRCA1, the latter being required for C286-mediated pain modulation, suggests that early DNA repair may be important to prevent phenotypic epigenetic imprints in NP. Thus, C286 is a promising drug candidate for neuropathic pain and DNA repair mechanisms may be useful therapeutic targets to explore.

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Phase 1 safety, tolerability, pharmacokinetics and pharmacodynamic results of KCL‐286, a novel retinoic acid receptor‐β agonist for treatment of spinal cord injury, in male healthy participants

Goncalves

Mant

Täubel³

et al. 2023

Brit J Clinical Pharma

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AimsKCL‐286 is an orally available agonist taht activates the retinoic acid receptor (RAR) β2, a transcription factor which stimulates axonal outgrowth. The investigational medicinal product is being developed for treatment of spinal cord injury (SCI). This adaptive dose escalation study evaluated the tolerability, safety and pharmacokinetics and pharmacodynamic activity of KCL‐286 in male healthy volunteers to establish dosing to be used in the SCI patient population.MethodsThe design was a double blind, randomized, placebo‐controlled dose escalation study in 2 parts: a single ascending dose adaptive design with a food interaction arm, and a multiple ascending dose design. RARβ2 mRNA expression was evaluated in white blood cells.ResultsAt the highest single and multiple ascending doses (100 mg), no trends or clinically important differences were noted in the incidence or intensity of adverse events (AEs), serious AEs or other safety assessments with none leading to withdrawal from the study. The AEs were dry skin, rash, skin exfoliation, raised liver enzymes and eye disorders. There was an increase in mean maximum observed concentration and area under the plasma concentration–time curve up to 24 h showing a trend to subproportionality with dose. RARβ2 was upregulated by the investigational medicinal product in white blood cells.ConclusionKCL‐286 was well tolerated by healthy human participants following doses that exceeded potentially clinically relevant plasma exposures based on preclinical in vivo models. Target engagement shows the drug candidate activates its receptor. These findings support further development of KCL‐286 as a novel oral treatment for SCI.

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Discovery and lead optimisation of a potent, selective and orally bioavailable RARβ agonist for the potential treatment of nerve injury

Abstract: Graphical abstract

Cited by 6 publications

References 9 publications

Recent advances in the design of RAR α and RAR β agonists as orally bioavailable drugs. A review

Recent advances in the design of RAR α and RAR β agonists as orally bioavailable drugs. A review

RARβ Agonist Drug (C286) Demonstrates Efficacy in a Pre-clinical Neuropathic Pain Model Restoring Multiple Pathways via DNA Repair Mechanisms

Phase 1 safety, tolerability, pharmacokinetics and pharmacodynamic results of KCL‐286, a novel retinoic acid receptor‐β agonist for treatment of spinal cord injury, in male healthy participants

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