Repinotan

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Repinotan
Repinotan.svg
Clinical data
Routes of
administration 		Oral
Legal status
Legal status
  • In general: uncontrolled
Identifiers
  • (R)-(−)-2-[4-[(chroman-2-ylmethyl)-amino]-butyl]-1,1-dioxo-benzo[d]isothiazolone
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C21H24N2O4S
Molar mass 400.49 g·mol−1
3D model (JSmol)
  • C1CC2=CC=CC=C2O[C@H]1CNCCCCN3C(=O)C4=CC=CC=C4S3(=O)=O
  • InChI=1S/C21H24N2O4S/c24-21-18-8-2-4-10-20(18)28(25,26)23(21)14-6-5-13-22-15-17-12-11-16-7-1-3-9-19(16)27-17/h1-4,7-10,17,22H,5-6,11-15H2/t17-/m1/s1 X mark.svgN
  • Key:YGYBFMRFXNDIPO-QGZVFWFLSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Repinotan (BAYx3702), an aminomethylchroman derivative, is a selective 5-HT1A receptor full agonist with high potency and efficacy. [1] [2] It has neuroprotective effects in animal studies, [3] [4] [5] and was trialed in humans for reducing brain injury following head trauma. [6] It was subsequently trialed up to phase II for treatment of stroke, but while side effects were mild and consisted mainly of nausea, repinotan failed to demonstrate sufficient efficacy to justify further clinical trials. [7] [8] [9] However, repinotan continues to be investigated for other applications, and was found to be effective at counteracting the respiratory depression produced by morphine, though with slight reduction in analgesic effects. [10]

Contents

Medical uses

Acute ischemic stroke

Repinotan was originally developed by Bayer Healthcare AG (Wuppertal, Germany) as an oral treatment for depression. [11] However, it was instead trialed as a candidate for reducing brain injury following head trauma. The drug was then examined as a preventative of secondary brain damage for ischemic stroke victims. Early trials showed repinotan's ability to reduce hippocampal CA1 and CA3 neuronal loss. Cortical tissue damage was also reduced. In addition, repinotan was shown to mitigate spatial learning deficits. [12] However, trials were discontinued due to repinotan's efficacy being insufficient. [13]

Respiratory depression

Repinotan Dose Relationship to Nociception Repinotan Dose Relationship to Nociception.png
Repinotan Dose Relationship to Nociception

Repinotan has presently been found to be effective at stopping respiratory depression caused by morphine. In addition, it represses nociception at high doses, but enhances nociception at small doses (0.2 micrograms/kg). [10] Repinotan may be applicable to Parkinson's disease, as it is able to reduce glutamate-induced excitotoxicity and thereby partially cell death. [14]

Additional uses

Another stroke medication trialed at the same time, piclozotan, is similar to repinotan in that it is also a serotonin receptor agonist. Other drugs included zonampanel, which acts as an AMPA receptor antagonist instead of a 5-HT1A receptor agonist and DP-b99. DP-b99 is a metal iron chelator. [15]

Side effects

Repinotan's side effects during trials as a treatment for ischemic stroke consisted mainly of serotonergic side effects including nausea and vomiting. The most common side effect was headache. Neurological worsening, cerebral hemorrhage, and brain edema were the most common severe effects. However, repinotan was generally shown to be safe. [16]

Its current investigation as an antagonist for respiratory depression caused by morphine has shown there to be no serious cardiovascular side effects. However, a slight decrease in blood pressure was a more minor effect. [10] Repinotan has been shown to induce miosis. [17]

Pharmacology

Pharmacodynamics

Repinotan HCI (BAYx3702) acts as a highly selective 5-HT1A receptor full agonist. [13] It is blocked by the specific 5-HT1A receptor antagonist, WAY-100135. [10]

Repinotan is believed to operate through neuronal hyperpolarization. [18] When repinotan first binds to both pre- and postsynaptic 5-HT1A receptors, G protein-coupled inwardly rectifying potasium channels (GIRKs) are activated. This leads to hyperpolarization, subsequent inhibition of neuron firing, and lowering of glutamate release, which allows neurons to be protected against overexcitation. This could explain repinotan's neuroprotective properties. [8]

In addition, the protein Bcl-2, the serotonergic glial growth factor S100B, and nerve growth factor are affected by repinotan. [8] Repinotan is able to suppress caspase-3 through MAPK and PKC alpha. [19] Apoptosis as a result of anoxia/reoxygenation and H2O2 treatment may also be inhibited. [20]

Repinotan has been found to bind with high to moderate affinity to the alpha-1 and alpha-2 adrenergic, 5-HT7 and 5-HT1D, dopamine D2 and D4, sigma, and 5-HT2C receptor. It is able to increase activity of VTA dopaminergic neurons and medial prefrontal cortex dopamine release. [21] [22]

Pharmacokinetics

Repinotan's primary route of administration is by intravenous injection. [13] It is able to cross the blood-brain barrier- a highly selective barrier that separates circulating blood from the brain's extracellular fluid. Diffusion acts as the driving force, which allows repinotan to cross in both directions. In addition, the drug is uncharged, which is consistent with the fact that it is able to pass the lipophilic and non-polar blood-brain barrier. [23]

Infusion rates of up to 150 microg/h are well received. [24] After infusion, the distribution equilibrium between plasma and brain is reached almost instantaneously. [23] Repinotan's efficacy is mainly dependent on factors such as the length of time between the start of stroke symptoms and taking the drug. The age and blood pressure of the patient also plays a role. Decreases in response with increasing age as well as decreases in response as blood pressure increases are generally observed. [25] The most efficient dose is approximately 1.25 mg per day. [16]

The half-life of repinotan is approximately 1 hour. Elimination ensues in parallel from plasma and brain. In addition, repinotan's volume of distribution at steady-state and plasma clearance are independent of dose. This is indicative of linear pharmacokinetics over the range of 0.1-3.0 micrograms repinotan/kg/h. [26]

its primary metabolizer is the CYP2D6 enzyme. Ethnic differences are known to have an effect on the rate of metabolism of the CYP2D6.[ citation needed ]

Sex and age do not have any influence on repinotan's pharmacokinetics. Bodyweight also does not play a big role. [24]

Chemistry

Properties

Repinotan is an enantiomerically pure aminomethyl chromane derivative with a saccharinyl butyl substituent. [27] It is classified as a synthetic organic and possesses five hydrogen bond acceptors and one hydrogen bond donor. Its topological polar surface area is 84.09 and it has seven rotatable bonds. In addition, its molecular weight is 400.15 g/mole. Repinotan has a formal charge of zero and a covalently-bonded unit count of one. It is similar in chemical and physical properties to the ligands quetiapine, PAT5A, and pioglitazone. [28]

Synthesis

Bayer Healthcare AG synthesized Repinotan in three main reaction sequences. A form with a metabolically stable 14carbon-label was necessary for pharmacokinetic studies. The hydrochloride was hydroxylated in the 6-position of the chromane moiety. [27]

For the first reaction sequence, [14C]-phenol was used as the starting compound. Michael adduct formation was then employed in the preparation of chromane rings with [14C]-phenol. [27]

In the second reaction sequence, [Carbonyl-14C]-2-hydroxy-acetophenone was used first. Compound XII was formed from condensation of [carbonyl-14C-]-2-hydroxy-acetophenone with dimethyl oxylate and ring closure. Hydrogenolytical debenzylation and hydrochloric acid created the final product. [27]

The third reaction involved intermediate XVII undergoing acylation using acetyl chloride. Deacetylation and debenzylation were then implemented with HCI. Pd/C was used in the deacetylation step and Pd/C was used in the debenzylation step. [27]

Patent ( Ex 92 ): Crystalline form: Radiolabelled: Revised: Repinotan synthesis.svg
Patent (Ex 92): Crystalline form: Radiolabelled: Revised:

The last step in the synthesis involves the reaction between (R)-2-aminomethylchroman [404337-71-9] (1) and N-(4-bromobutyl)saccharin [103564-59-6] (2).

History

Bayer Healthcare AG (Wuppertal, Germany) first synthesized repinotan during early 2000s. As of 2004, it was expected to be filed by the NDA. Phase III trials for both ischemic stroke and traumatic brain injury were run in March 2002. [11] However, these trials found the drug ineffective as a treatment (November, 2009). [13]

In October 2010, further investigation showed repinotan able to counteract respiratory depression caused by morphine. Repinotan continues to be examined, but has not yet been commercially released. [10]

Currently, repinotan is not commercially available in the United States. Sales of $1000 million in the U.S. and a launch date of 2006 were originally anticipated by Lehman Brothers. Bank Vontobel and Bayer both estimated sales of 450 million euros. However, the drug continues to be under investigation for different treatments than its original intent. [11]

See also

References

  1. ↑ De Vry J, Schohe-Loop R, Heine HG, Greuel JM, Mauler F, Schmidt B, et al. (March 1998). "Characterization of the aminomethylchroman derivative BAY x 3702 as a highly potent 5-hydroxytryptamine1A receptor agonist". The Journal of Pharmacology and Experimental Therapeutics. 284 (3): 1082–1094. doi:10.1016/S0022-3565(24)37340-9. PMID   9495870.
  2. ↑ Dong J, de Montigny C, Blier P (September 1998). "Full agonistic properties of BAY x 3702 on presynaptic and postsynaptic 5-HT1A receptors electrophysiological studies in the rat hippocampus and dorsal raphe". The Journal of Pharmacology and Experimental Therapeutics. 286 (3): 1239–1247. doi:10.1016/S0022-3565(24)37717-1. PMID   9732384.
  3. ↑ Alessandri B, Tsuchida E, Bullock RM (October 1999). "The neuroprotective effect of a new serotonin receptor agonist, BAY X3702, upon focal ischemic brain damage caused by acute subdural hematoma in the rat". Brain Research. 845 (2): 232–235. doi:10.1016/S0006-8993(99)01948-4. PMID   10536203. S2CID   36341439.
  4. ↑ Kline AE, Yu J, Horváth E, Marion DW, Dixon CE (2001). "The selective 5-HT(1A) receptor agonist repinotan HCl attenuates histopathology and spatial learning deficits following traumatic brain injury in rats". Neuroscience. 106 (3): 547–555. doi:10.1016/S0306-4522(01)00300-1. PMID   11591455. S2CID   54308982.
  5. ↑ Mauler F, Horváth E (April 2005). "Neuroprotective efficacy of repinotan HCl, a 5-HT1A receptor agonist, in animal models of stroke and traumatic brain injury". Journal of Cerebral Blood Flow and Metabolism. 25 (4): 451–459. doi: 10.1038/sj.jcbfm.9600038 . PMID   15674237.
  6. ↑ Ohman J, Braakman R, Legout V, et al. (Traumatic Brain Injury Study Group) (December 2001). "Repinotan (BAY x 3702): a 5HT1A agonist in traumatically brain injured patients". Journal of Neurotrauma. 18 (12): 1313–1321. doi:10.1089/08977150152725614. PMID   11780862.
  7. ↑ Lutsep HL (April 2005). "Repinotan, A 5-HT1A agonist, in the treatment of acute ischemic stroke". Current Drug Targets. CNS and Neurological Disorders. 4 (2): 119–120. doi:10.2174/1568007053544165. PMID   15857296.
  8. 1 2 3 Berends AC, Luiten PG, Nyakas C (2005). "A review of the neuroprotective properties of the 5-HT1A receptor agonist repinotan HCl (BAYx3702) in ischemic stroke". CNS Drug Reviews. 11 (4): 379–402. doi:10.1111/j.1527-3458.2005.tb00055.x. PMC   6741728 . PMID   16614737.
  9. ↑ Teal P, Davis S, Hacke W, Kaste M, Lyden PD, Fierus M, et al. (Modified Randomized Exposure Controlled Trial Study Investigators) (November 2009). "A randomized, double-blind, placebo-controlled trial to evaluate the efficacy, safety, tolerability, and pharmacokinetic/pharmacodynamic effects of a targeted exposure of intravenous repinotan in patients with acute ischemic stroke: modified Randomized Exposure Controlled Trial (mRECT)". Stroke. 40 (11): 3518–3525. doi: 10.1161/STROKEAHA.109.551382 . hdl: 2078.1/123821 . PMID   19745176.
  10. 1 2 3 4 5 Guenther U, Wrigge H, Theuerkauf N, Boettcher MF, Wensing G, Zinserling J, et al. (October 2010). "Repinotan, a selective 5-HT1A-R-agonist, antagonizes morphine-induced ventilatory depression in anesthetized rats". Anesthesia and Analgesia. 111 (4): 901–907. doi: 10.1213/ANE.0b013e3181eac011 . PMID   20802053. S2CID   39217801.
  11. 1 2 3 Lutsep HL (June 2002). "Repinotan Bayer". Current Opinion in Investigational Drugs. 3 (6): 924–927. PMID   12137415.
  12. ↑ Kline AE, Yu J, Horváth E, Marion DW, Dixon CE (2001). "The selective 5-HT(1A) receptor agonist repinotan HCl attenuates histopathology and spatial learning deficits following traumatic brain injury in rats". Neuroscience. 106 (3): 547–555. doi:10.1016/s0306-4522(01)00300-1. PMID   11591455. S2CID   54308982.
  13. 1 2 3 4 Teal P, Davis S, Hacke W, Kaste M, Lyden PD, Fierus M (November 2009). "A randomized, double-blind, placebo-controlled trial to evaluate the efficacy, safety, tolerability, and pharmacokinetic/pharmacodynamic effects of a targeted exposure of intravenous repinotan in patients with acute ischemic stroke: modified Randomized Exposure Controlled Trial (mRECT)". Stroke. 40 (11): 3518–3525. doi: 10.1161/strokeaha.109.551382 . hdl: 2078.1/123821 . PMID   19745176.
  14. ↑ Bezard E, Gerlach I, Moratalla R, Gross CE, Jork R (July 2006). "5-HT1A receptor agonist-mediated protection from MPTP toxicity in mouse and macaque models of Parkinson's disease". Neurobiology of Disease. 23 (1): 77–86. doi:10.1016/j.nbd.2006.02.003. hdl:10261/59551. PMID   16545572. S2CID   19803633.
  15. ↑ Ferro JM, Dávalos A (2006). "Other neuroprotective therapies on trial in acute stroke". Cerebrovascular Diseases. 21 Suppl 2 (2): 127–130. doi:10.1159/000091712. PMID   16651823. S2CID   39193793.
  16. 1 2 Teal P, Silver FL, Simard D (February 2005). "The BRAINS study: safety, tolerability, and dose-finding of repinotan in acute stroke". The Canadian Journal of Neurological Sciences. Le Journal Canadien des Sciences Neurologiques. 32 (1): 61–67. doi: 10.1017/s0317167100016899 . PMID   15825548.
  17. ↑ Boettcher M, Heinig R, Wensing G, Kuhlmann J (March 2005). "Pupil reaction: a valid sensitive clinical biomarker for 5-HT compounds". Basic & Clinical Pharmacology & Toxicology. 96 (3): 246. doi:10.1111/j.1742-7843.2005.pto960317.x. PMID   15733223.
  18. ↑ Tanigawa T, Heinig R, Kuroki Y, Higuchi S (February 2006). "Evaluation of interethnic differences in repinotan pharmacokinetics by using population approach" (PDF). Drug Metabolism and Pharmacokinetics. 21 (1): 61–69. doi:10.2133/dmpk.21.61. PMID   16547395. S2CID   10517194. Archived from the original (PDF) on 2020-02-07.
  19. ↑ De Vry J, Schohe-Loop R, Heine HG, Greuel JM, Mauler F, Schmidt B, et al. (March 1998). "Characterization of the aminomethylchroman derivative BAY x 3702 as a highly potent 5-hydroxytryptamine1A receptor agonist". The Journal of Pharmacology and Experimental Therapeutics. 284 (3): 1082–1094. doi:10.1016/S0022-3565(24)37340-9. PMID   9495870.
  20. ↑ Adayev T, Ray I, Sondhi R, Sobocki T, Banerjee P (April 2003). "The G protein-coupled 5-HT1A receptor causes suppression of caspase-3 through MAPK and protein kinase Calpha". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1640 (1): 85–96. doi: 10.1016/s0167-4889(03)00023-5 . PMID   12676358.
  21. ↑ Díaz-Mataix L, Artigas F, Celada P (May 2006). "Activation of pyramidal cells in rat medial prefrontal cortex projecting to ventral tegmental area by a 5-HT1A receptor agonist". European Neuropsychopharmacology. 16 (4): 288–296. doi:10.1016/j.euroneuro.2005.10.003. hdl:10261/34586. PMID   16290106. S2CID   38788669.
  22. ↑ Díaz-Mataix L, Scorza MC, Bortolozzi A, Toth M, Celada P, Artigas F (November 2005). "Involvement of 5-HT1A receptors in prefrontal cortex in the modulation of dopaminergic activity: role in atypical antipsychotic action". The Journal of Neuroscience. 25 (47): 10831–10843. doi:10.1523/jneurosci.2999-05.2005. PMC   6725886 . PMID   16306396.
  23. 1 2 Schwarz T, Beckermann B, Buehner K, Mauler F, Schuhmacher J, Seidel D, et al. (September 2005). "Pharmacokinetics of repinotan in healthy and brain injured animals". Biopharmaceutics & Drug Disposition. 26 (6): 259–268. doi:10.1002/bdd.458. PMID   15966026. S2CID   25596274.
  24. 1 2 Heinig R, Böttcher MF (2005). "Pharmacokinetics of escalating doses of intravenous repinotan in healthy male volunteers". Clinical Drug Investigation. 25 (2): 115–123. doi:10.2165/00044011-200525020-00004. PMID   17523761. S2CID   23415230.
  25. ↑ Teal P, Davis S, Hacke W, Kaste M, Lyden PD, Fierus M (November 2009). "A randomized, double-blind, placebo-controlled trial to evaluate the efficacy, safety, tolerability, and pharmacokinetic/pharmacodynamic effects of a targeted exposure of intravenous repinotan in patients with acute ischemic stroke: modified Randomized Exposure Controlled Trial (mRECT)". Stroke. 40 (11): 3518–3525. doi: 10.1161/STROKEAHA.109.551382 . hdl: 2078.1/123821 . PMID   19745176.
  26. ↑ Heinig R, Sundaresan P, Shah A, Boettcher M (2005). "Effect of gender and age on the pharmacokinetics of repinotan". Clinical Drug Investigation. 25 (2): 125–134. doi:10.2165/00044011-200525020-00005. PMID   17523762. S2CID   40485277.
  27. 1 2 3 4 5 6 Seidel D, Conrad M, Schoof Y, Schohe-Loop R (November 2002). "Synthesis of [14C]-labelled repinotan hydrochloride and its major metabolite M-6". Journal of Labelled Compounds and Radiopharmaceuticals. 45 (13): 1115–1132. doi:10.1002/jlcr.629.
  28. ↑ "PubChem- Repinotan". PubChem. National Center for Biotechnology Information, U.S. National Library of Medicine. Retrieved 10 November 2014.
  29. ↑ US 5300523,Junge B, Schohe R, Seidel PR, Glaser T, Traber J, Benz U, Schuurman T, De Vry JM,issued 1994, assigned to Bayer Healthcare AG.
  30. ↑ US 5830908,Grunenberg A, Brehm O, Conrad M, Seidel D,issued 1998, assigned to Bayer AG.
  31. ↑ Gross JL (November 2003). "A concise stereospecific synthesis of repinotan (BAY× 3702)". Tetrahedron Letters. 44 (47): 8563–8565. doi:10.1016/j.tetlet.2003.09.130.
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