<i>In vitro</i>metabolism and<i>in vivo</i>pharmacokinetics of quinoline 3-carboxamide derivatives in various species

Tuvesson, Helén; Hallin, Ingrid; Ellman, Marianne; Sparre, Birgitta; Gunnarsson, P. O.; Seidegård, Janeric

doi:10.1080/00498250500066329

Cited by 7 publications

(2 citation statements)

References 19 publications

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“…LAQ is metabolized partly by N-dealkylation to give the potent AHR agonist DELAQ (deethylated LAQ; IMA-06201) in minute amounts [41]. The prodrug IMA-08401 (henceforth referred to as C2) is a diacetyl prodrug of DELAQ, representing a novel selective AHR modulator designed to effectively hydrolyze to DELAQ in vivo (to a far greater extent than LAQ) and being a potent agonist of the AHR [42].…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic Impact of IMA-08401, a Novel AHR Agonist Resembling Laquinimod, on Rat Liver

Prokopec

Pohjanvirta

Mahiout

et al. 2019

IJMS

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IMA-08401 (C2) is a novel aryl hydrocarbon receptor (AHR) agonist and selective AHR modulator (SAHRM) that is structurally similar to laquinimod (LAQ). Both compounds are converted to the AHR-active metabolite DELAQ (IMA-06201) in vivo. SAHRMs have been proposed as therapeutic options for various autoimmune disorders. Clinical trials on LAQ have not reported any significant toxic outcomes and C2 has shown low toxicity in rats; however, their functional resemblance to the highly toxic AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) raises questions. Here, we characterize the hepatic transcriptomic changes induced by acute (single-dose) and subacute exposure (repeated dosing for 5 days followed by a 5-day recovery period) to C2 in Sprague-Dawley rats. Exposure to C2 leads to activation of the AHR, as shown by altered transcription of Cyp1a1. We identify a heightened response early after exposure that drops off by day 10. Acute exposure to C2 leads to changes to transcription of genes involved in antiviral and antibacterial responses, which highlights the immunomodulator effects of this AHR agonist. Subacute exposure causes an oxidative stress response in the liver, the consequences of which require further study on target tissues such as the CNS and immune system, both of which may be compromised in this patient population.

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Section: Introductionmentioning

confidence: 99%

Transcriptomic Impact of IMA-08401, a Novel AHR Agonist Resembling Laquinimod, on Rat Liver

Prokopec

Pohjanvirta

Mahiout

et al. 2019

IJMS

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“…The half-life is 80 hours and peak plasma concentration is within one hour. 21 A high proportion of the drug in circulation is protein-bound; in plasma only 1.4% is unbound. Drug-interaction studies with these agents will help determine whether these potential interactions are clinically relevant and whether dose adjustments may be needed.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Laquinimod in Relapsing–Remitting Multiple Sclerosis

Jeffery¹,

Pharr²,

Zeid³

2010

US Neurology

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Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that affects at least 400,000 people in the US alone. Estimates of the prevalence of MS were made in the early 1990s and may vastly underestimate the true prevalence of the disease.1,2 The cause of MS remains unknown, but it is clear that inflammatory demyelination and axonal damage lead to considerable disability in both early-and late-stage disease. The rate and extent of disability progression are highly variable.The mainstay of MS treatment over the past 17 years has primarily been treatment with interferons (IFNs) and glatiramer acetate. IFNβ-1b AbstractLaquinimod is a novel oral immunomodulatory agent in development for the treatment of relapsing-remitting multiple sclerosis (RRMS). It is a derivative of roquinimex that was structurally altered to maximize safety and efficacy. In animal models laquinimod was far more potent than its parent compound with no apparent propensity to induce inflammatory reactions. Laquinimod is a broad-spectrum immunomodulatory agent with a multitude of effects on the immune system but no effect on the ability of animals to mount a cellular or humoral immune response. In phase II trials selected for highly active RRMS patients, laquinimod reduced the frequency of gadolinium-enhancing lesions by 55%, significantly reduced the number of new T 2 lesions, and had a trend toward an effect on reducing brain volume loss. Laquinimod was well tolerated in phase II trials and had a favorable safety profile with a paucity of adverse events. It is metabolized by the cytochrome P-450 system (CYP-3A4) and may interact with some compounds used in symptomatic therapy. With a favorable efficacy and safety profile, laquinimod is a potential first-line agent in the future treatment of RRMS. KeywordsMultiple sclerosis, laquinimod, immunomodulatory, safety, efficacy Disclosure: Douglas R Jeffery, MD, PhD, has received honoraria for speaking and consulting from Teva, Bayer, Biogen-Idec, Novartis, Serono, Pfizer, Acorda, and GSK, and has received research support from Teva, Bayer, Biogen-Idec, Serono, Novartis, and Pfizer. The remaining authors have no conflicts of interest to declare.

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Inhibition of the development of chronic experimental autoimmune encephalomyelitis by laquinimod (ABR-215062) in IFN-β k.o. and wild type mice

Runström

Leanderson

Ohlsson³

et al. 2006

Journal of Neuroimmunology

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In vitrometabolism andin vivopharmacokinetics of quinoline 3-carboxamide derivatives in various species

Cited by 7 publications

References 19 publications

Transcriptomic Impact of IMA-08401, a Novel AHR Agonist Resembling Laquinimod, on Rat Liver

Transcriptomic Impact of IMA-08401, a Novel AHR Agonist Resembling Laquinimod, on Rat Liver

Laquinimod in Relapsing–Remitting Multiple Sclerosis

Inhibition of the development of chronic experimental autoimmune encephalomyelitis by laquinimod (ABR-215062) in IFN-β k.o. and wild type mice

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