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isaxonine (isaxonine / Nerfactor)

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Ipsen Pharma · Small Molecule · Small Molecule

What is isaxonine?

isaxonine is a small molecule developed by Ipsen Pharma. It is approved for therapeutic indications.

Drug Profile

Brand Namesisaxonine, Nerfactor
CompanyIpsen Pharma
Drug ClassSmall Molecule
StatusApproved
Sources: ClinicalTrials.gov, Ipsen Pharma

Related Research Articles

PubMedToxicology letters1994-09-01

Paracetamol potentiates isaxonine toxicity in vitro.

Shrivastava R R, John G G, Chevalier A A, Beaughard M M et al.

The toxicity of isaxonine alone and in combination with the known glutathione depletor, paracetamol, was evaluated using rat hepatocyte primary cultures in vitro by measuring morphometric parameters and the leakage of intracellular lactate dehydrogenase into the culture medium. No cytotoxicity was observed with isaxonine at concentrations up to 10(-3) M, whereas paracetamol was cytotoxic at concentrations above 0.6 x 10(-3) M in the culture medium. Paracetamol cytotoxicity (0.6-3.3 x 10(-3) M) was enhanced in the presence of a non-cytotoxic concentration of isaxonine (10(-7) M). Furthermore cytotoxicity was observed when cells were exposed to a combination of non-cytotoxic concentrations of the paracetamol (0.3 x 10(-3) M) and isaxonine (10(-7) M). These findings demonstrate that isaxonine has no direct cytotoxic effect even at high concentrations. However co-administration of isaxonine with paracetamol greatly potentiates cytotoxicity. We suggest that this effect may be related to glutathione depletion within the cell but additional studies are required to verify this hypothesis.

PMID 8091425
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PubMedNeuroscience letters1993-04-02

Neurite outgrowth of neurons of rat dorsal root ganglia induced by new neurotrophic substances with guanidine group.

Lehmann S S, Quirosa-Guillou C C, Becherer U U, Thal C C et al.

In order to search for compounds mimicking the neurotrophic activities, a series of substances possessing the guanidine group of isaxonine (2-isopropylamino-pyrimidine), were synthesized and tested for their ability to induce neurite outgrowth in cultures of explants of rat dorsal root ganglia. It is reported that several of these compounds, at concentrations ranging from 10(-5) to 10(-7) M, showed important effects on neurite outgrowth in vitro, similar to that obtained with the nerve growth factor NGF. These effects were found to be additive to that of NGF.

PMID 8515880
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PubMedBiological & pharmaceutical bulletin1993-03-01

Neurotropic pyrimidine heterocyclic compounds. I. The newly synthesized pyrimidine compounds promote neurite outgrowth of GOTO and neuro 2a neuroblastoma cell lines, and potentiate nerve growth factor (NGF)-induced neurite sprouting of PC 12 cells.

Awaya A A, Kobayashi H H, Horikomi K K, Tanaka S S et al.

From the study using cultured human and mouse neuroblastoma cells, we found that a new type of synthetic bicyclic pyrimidine compounds possessing piperazine moiety strongly promoted neurite outgrowth in neuroblastoma cell lines human GOTO and mouse neuro 2a. The most effective compounds of these 2-piperazinopyrimidine derivatives possessing nerve growth factor (NGF)-like activity were 2-piperazino-6-oxo-5,6-dihydro(7H)pyrrolo[2,3-d]pyrimidine and 2-piperadino-6-methyl-5-oxo-5,6-dihydro(7H)pyrrolo[3,4-d]pyrimidin e. The piperazinopyrimidine compounds were also shown to potentiate NGF-induced neurite sprouting of rat pheochromocytoma PC12 cells. The compounds were more effective in cell cultures than isopropylaminopyrimidine (isaxonine) which had been previously developed and then withdrawn. We discussed the merit of the method of the screening of neurotropic compounds by neurite sprouting activity in cultured neuroblastoma cells.

PMID 8364468
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PubMedEuropean journal of pharmacology1992-05-01

In vitro metabolism of isaxonine phosphate: formation of two metabolites, 5-hydroxyisaxonine and 2-aminopyrimidine, and covalent binding to microsomal proteins.

Martinat C C, Amar C C, Dansette P M PM, Leclaire J J et al.

Isaxonine phosphate or Nerfactor (2-isopropylaminopyrimidine) has been implicated in several cases of hepatitis which is reversible after withdrawal of the drug. In order to understand the cause of such hepatitis, the metabolic activation of isaxonine phosphate with different liver microsomes was investigated. The major metabolites were 5-hydroxyisopropylaminopyrimidine and 2-aminopyrimidine. Covalent binding to microsomal proteins was also detected. In vitro metabolic activation required intact microsomes, NADPH and O2 as cofactors and was cytochrome P-450 dependent. A sensitive fluorimetric assay of 5-hydroxyisaxonine was developed. The metabolism of isaxonine phosphate was compared in liver microsomes from rat, rabbit, dog, monkey and man and found to be qualitatively similar. Treatment of rats with phenobarbital increased the formation of 5-hydroxyisaxonine, while treatment with 3-methylcholanthrene increased the formation of 2-aminopyrimidine but decreased that of 5-hydroxyisaxonine. Inhibition and reconstitution experiments demonstrated that 5-hydroxylation of isaxonine was catalyzed by a cytochrome P-450. Metabolic oxidation of isaxonine phosphate using 5-[3H]isaxonine phosphate led to a total loss of tritium in 5-hydroxyisaxonine and partial loss of tritium in 2-aminopyrimidine and covalent binding to proteins.

PMID 1397069
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PubMedBritish journal of pharmacology1991-05-01

Putative neurotrophic factors and functional recovery from peripheral nerve damage in the rat.

Van der Zee C E CE, Brakkee J H JH, Gispen W H WH

1. In rats, recovery of sensory-motor function following a crush lesion of the sciatic or tibial nerve was monitored by measuring foot reflex withdrawal from a local noxious stimulation of the foot sole. 2. Putative neurotrophic compounds were tested on this functional recovery model: melanocortins (peptides derived from ACTH (corticotropin) and alpha-MSH (melanotropin], gangliosides and nimodipine were effective whereas isaxonine and TRH (thyrotropin releasing hormone) were not. 3. Structure-activity studies with melanocortins revealed a similar effectiveness of alpha-MSH, [N-Leu4, D-Phe7]-alpha-MSH, desacetyl-alpha-MSH and the ACTH analogue ORG 2766, questioning the validity of the previously suggested notion that the melanotrophic properties of these peptides are responsible for their neurotrophic effect. 4. As recovery of function after peripheral nerve damage follows a similar time course in hypophysectomized (five days post operation) and sham-operated rats, effective melanocortin therapy does not mimic an endogenous peptide signal in the repair process from pituitary origin. 5. Subcutaneous treatment with ORG 2766 (7.5 micrograms kg-1 48 h-1) facilitates recovery of function following peripheral nerve damage in young (6-7 weeks old), mature (5 month old) and old (20 month old) rats. 6. In view of the diversity in structure of the effective neurotrophic factors and the complexity of nerve repair, the present data support the notion that peripheral nerve repair may be facilitated by different humoral factors likely to be active on different aspects of the recovery process.

PMID 1678980
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PubMedHepatology (Baltimore, Md.)1989-05-01

Presence of covalently bound metabolites on rat hepatocyte plasma membrane proteins after administration of isaxonine, a drug leading to immunoallergic hepatitis in man.

Loeper J J, Descatoire V V, Amouyal G G, Lettéron P P et al.

Isaxonine and several other drugs transformed by cytochrome P-450 into reactive metabolites apparently lead to immunoallergic hepatitis in man. Protein epitopes modified by the covalent binding of the metabolites have been proposed as possible targets for the immune response. The purpose of this work was to determine whether covalently bound metabolites are indeed present on hepatocyte plasma membrane proteins. In a first series of experiments, rats were killed 15 or 60 min after administration of [2-14C]isaxonine (0.2 mmol.kg-1 i.p.), and various fractions were prepared from isolated hepatocytes; microsomal contamination of the plasma membrane fraction was 1.2% or less. At 60 min, the amount of isaxonine metabolite covalently bound per mg of protein was similar in plasma membranes (0.42 nmole metabolite.mg protein-1) and in microsomes (0.38); both values were decreased by about 70% in rats pretreated with piperonyl butoxide, an inhibitor of cytochrome P-450. At 15 min, however, covalent binding to plasma membrane proteins (0.06 nmole metabolite.mg protein-1) was only half of that to microsomal proteins (0.12). In a second series of experiments, [2-14C] isaxonine (0.1 mM) was incubated with NADPH, hepatic microsomes and plasma membranes. The reactive isaxonine metabolite became bound extensively to microsomal proteins, but not to plasma membrane proteins. These results show that administration of isaxonine leads to the presence of isaxonine adducts on the proteins of the hepatocyte plasma membrane.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID 2707734
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