Repinotan

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Repinotan
Repinotan.png
Systematic (IUPAC) name
(R)-(-)-2-[4-[(chroman-2-ylmethyl)-amino]-butyl]-1,1-dioxo-benzo[d]isothiazolone
Clinical data
Legal status
  • Uncontrolled
Routes Oral
Identifiers
CAS number 144980-29-0 YesY
ATC code ?
PubChem CID 198757
UNII 05PB82Z52L N
ChEMBL CHEMBL1614652 N
Chemical data
Formula C21H24N2O4S 
Mol. mass 400.491 g/mol
 N (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 trialled in humans for reducing brain injury following head trauma.[6] It was subsequently trialled 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]

History[edit]

Repinotan was first synthesized by Bayer Healthcare AG (Wuppertal, Germany) during the early 2000s. In June 2001, NDA filling was expected by 2004. During March 2002, the drug underwent phase III trials for both ischemic stroke and traumatic brain injury.[11] However, during November 2009, it was found to be ineffective for these treatments.[12]

Further investigation in October 2010 found repinotan able to counteract respiratory depression produced by morphine. Repinotan continues to be examined, but as of November 2014 has not been commercially released.[13]

Chemical and Physical Properties[edit]

2-D Structure of Repinotan Hydrochloride

Repinotan is an enantiomerically pure aminomethyl chromane derivative with a saccharinylbutyl substituent.[14] 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.[15]

Synthesis[edit]

Repinotan was originally synthesized by Bayer Healthcare AG (Wuppertal, Germany). A metabolically stable 14carbon-label in the chromane moiety was required for studies of repinotan’s pharmacokinetics. The synthesis was completed in three main reactions.[14]

First Reaction Scheme[edit]

For the first reaction, [14C]-phenol was used as the starting compound. It was used for the known preparation of chromane rings via Michael adduct formation in the first labeling synthesis. The 14carbon labeled metabolite M-6 of repinotan was synthesized as the hydrochloride and hydroxylated in the 6-position of the chromane moiety.[14]

Second Reaction Scheme[edit]

The second reaction was started from commercially available [carbonyl-14C]-2-hydroxy-acetophenone. Condensation with dimethyl oxalate and subsequent ring closure gave compound XII. The final product was formed by hydrogenolytical debenzylation and subsequent addition of hydrochloric acid.[14]

Third Reaction Scheme[edit]

The third reaction involved labeled intermediate XVII being subjected to acylation with acetyl chloride. Deacetylation and debenzylation steps were carried out using HCI, Pd/C in the first step, and H2, Pd/C in the second step. The desired product was obtained after purification by semi-preparative HPLC.[14]

Mechanism of Action[edit]

Repinotan hydrochloride (BAYx3702) is a highly selective 5-HT1A receptor full agonist. It is blocked by the specific 5-HT1A receptor antagonist, WAY 1006345[16] and its primary metabolizer is CYP2D6. CYP2D6 is known to be subject to ethnic differences and is believed to act by neuronal hyperpolarization.[17]

When repinotan first binds to both pre- and post-synaptic 5-HT1A receptors, G protein-coupled inwardly rectifying K+ channels are activated. This causes hyperpolarization. Because hyperpolarization results in the inhibition of neuron firing and the reduction of glutamate release, these mechanisms could explain the neuroprotective efficacy of repinotan by leading to protection of neurons against overexcitation.[18]

In addition, repinotan affects the death-inhibiting protein Bcl-2, the serotonergic glial growth factor S-100beta, and Nerve Growth Factor. It also suppresses the activity of caspase-3 through MAPK and PKCalpha,[19] and blocks apoptosis caused by anoxia/reoxygenation and H(2)O(2) treatment.[20]

Repinotan has been found to bind with relatively high to moderate affinity to the receptors alpha-1 and alpha-2 adrenergic, 5-HT7- and 5-HT1D, dopamine D2 and D4, sigma sites, and 5-HT2C.[21] It is able to increase the activity of dopaminergic neurons in the ventral segmental area (VTA) as well as dopamine release into the VTA and medial prefrontal cortex. It has been suggested that repinotan may modulate the activity of VTA dopaminergic neurons. This may be done through a change in the pyramidal output of medial prefrontal cortex neurons projecting to the VTA.[22]

Pharmacology[edit]

Pharmacodynamics[edit]

Repinotan hydrochloride acts as a selective high-affinity full receptor agonist at the 5-HT1A receptor subtype.[12] 5-HT1A receptor agonists act by increasing the activity of dopamine (DA) neurons in the ventral segmental area as well as DA release in the medial prefrontal cortex (a 5-HT1A receptor-rich area).[23]

Additionally, it is an extremely potent drug and is able to cross the blood-brain barrier. The distribution equilibrium between plasma and brain is reached almost immediately after the start of infusion and it is highly potent.[24]

Repinotan’s efficacy is mainly dependent on factors such as the delay between the onset of stroke symptoms and the start of repinotan. The age and blood pressure of the patient also play a role. Decreases in response with increasing age and decreases in response as blood pressure increases are generally observed.[25] The most efficient dose of repinotan is approximately 1.25 mg/dose.[26]

Pharmacokinetics[edit]

Repinotan’s primary route of administration is by intravenous injection, which indicates that it goes directly into the bloodstream.[13] It is able to cross the blood-brain barrier- a highly selective permeability barrier that separates the circulating blood from the extracellular fluid of the brain in the central nervous system.[12] Repinotan crosses freely in both directions with diffusion as the driving force. In addition, it is uncharged, which is consistent with the fact that it able to pass the lipophilic and non-polar blood-brain barrier.[12]

The half-life of repinotan is approximately 1 hour. Elimination occurs in parallel from plasma and brain and its volume of distribution at steady-state and plasma clearance is independent of dose. This is indicative of linear pharmacokinetics and dose-proportionality over the dose range of 0.1-3.0 micrograms/kg/h.[27]

Repinotan is well-tolerated at infusion rates of up to 150 microg/h. The optimum dose of repinotan is approximately 5 to 20 micrograms/L in plasma and it has been shown to have neuroprotective effects when given at the frequency of 0.3-100 micrograms/kg/h. 1.25 mg/day is the optimal dose.[12]

Potential Effects of Gender, Age, and Interethnic Differences on Repinotan Administration[edit]

CYP2D6, the primary metabolizer of repinotan, has been found to be subject to polymorphism and ethnic differences. Gender and age were shown to have no influence on repinotan’s pharmacokinetics.[28] Bodyweight also did not have a major influence.[29]

Treatment[edit]

Acute Ischemic Stroke[edit]

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 established in rodent model preclinical studies as a preventative of secondary brain damage in brain-injured patients suffering from acute ischemic stroke. Early trials showed repinotan’s ability to reduce hippocampal CA1 and CA3 neuronal loss and cortical tissue damage. It was also shown to attenuate spatial learning deficits following controlled cortical impact injury.[30] However, trials were discontinued due to repinotan’s efficacy being insufficient.[12]

Respiratory Depression[edit]

Currently, repinotan has been found to be effective at antagonizing morphine-induced ventilatory depression. At small doses it has pronociceptive effects and has been found to prolong anitonociception (reduced sensitivity to painful stimuli). However, it has not been found to depress nociception itself. Instead, it suppresses nociception at higher doses, but enhances nociception at smaller doses.[13] Repinotan may be applicable to Parkinson’s, as it is able to reduce glutamate-induced excitotoxicity and excitoxicity-mediated cell death.[31]

Additional Medications Trialed[edit]

Another stroke medication trialed at the same time, piclozotan, is similar to repinotan in that it is a serotonin agonist, which also interferes with the ischemic cascade. 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. These drugs were found to act even worse as stroke medications than was repinotan and trials were discontinued.[32]

Side Effects[edit]

Repinotan’s side effects during trials as a preventative of secondary brain damage in brain-injured patients suffering from acute ischemic stroke consisted mainly of serotonergic side effects such as nausea and vomiting. The most common side effect was headache. The most common severe adverse effects were neurological worsening, cerebral hemorrhagne, and brain edema. However, the general profile was determined to be safe and well-tolerated.[33]

Its current investigation as an antagonist for morphine-induced depression of ventilation has shown there to be no serious cardiovascular side effects at an optimum dose of 20 micrograms/kg. However, a slight decrease in mean arterial blood pressure was a more minor effect.[13] Repinotan concentration has been correlated with a reduction in pupil diameter.[34]

Original Predictions and Current Availability[edit]

Currently, repinotan is not commercially available in the United States. Lehman Brothers originally predicted a launch date of 2006 in March 2002 and estimated peak sales of $1000 million in the U.S. alone. A 20 to 30% probability of the drug reaching market was also anticipated. Bank Vontobel estimated a launch date of 2006 as well with potential sales of 450 million Euros in its fifth year of sales. Bayer also predicted peak sales of 450 million Euros. The company expected to launch repinotan throughout Europe and the US in 2006. However, the drug continues to be under investigation for different clinical treatments other than its original intent.[11]

See also[edit]

References[edit]

  1. ^ De Vry, J.; Schohe-Loop, R.; Heine, H. G.; Greuel, J. M.; Mauler, F.; Schmidt, B.; Sommermeyer, H.; Glaser, T. (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. PMID 9495870.  edit
  2. ^ Dong, J.; De Montigny, C.; Blier, P. (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. PMID 9732384.  edit
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  5. ^ Mauler, F.; Horváth, E. (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 : official journal of the International Society of Cerebral Blood Flow and Metabolism 25 (4): 451–459. doi:10.1038/sj.jcbfm.9600038. PMID 15674237.  edit
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  18. ^ Berends, AC; Luiten, PG; Nyakas, C (NaN). "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. PMID 16614737.  Check date values in: |date= (help)
  19. ^ De Vry, J; Schohe-Loop, R; Heine, HG; Greuel, JM; Mauler, F; Schmidt, B; Sommermeyer, H; Glaser, T (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): 1082–94. PMID 9495870. 
  20. ^ Adayev, T; Ray, I; Sondhi, R; Sobocki, T; Banerjee, P (7 April 2003). "The G protein-coupled 5-HT1A receptor causes suppression of caspase-3 through MAPK and protein kinase Calpha.". Biochimica et biophysica acta 1640 (1): 85–96. PMID 12676358. 
  21. ^ De Vry, J; Schohe-Loop, R; Heine, HG; Greuel, JM; Mauler, F; Schmidt, B; Sommermeyer, H; Glaser, T (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): 1082–94. PMID 9495870. 
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  25. ^ 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 : official journal of the International Society of Cerebral Blood Flow and Metabolism 25 (4): 451–9. PMID 15674237. 
  26. ^ 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): 61–7. PMID 15825548. 
  27. ^ Heinig, R; Sundaresan, P; Shah, A; Boettcher, M (2005). "Effect of gender and age on the pharmacokinetics of repinotan.". Clinical drug investigation 25 (2): 125–34. PMID 17523762. 
  28. ^ Tanigawa, T; Heinig, R; Kuroki, Y; Higuchi, S (February 2006). "Evaluation of interethnic differences in repinotan pharmacokinetics by using population approach.". Drug metabolism and pharmacokinetics 21 (1): 61–9. PMID 16547395. 
  29. ^ Guenther, U; Theuerkauf, NU; Huse, D; Boettcher, MF; Wensing, G; Putensen, C; Hoeft, A (January 2012). "Selective 5-HT(1A)-R-agonist repinotan prevents remifentanil-induced ventilatory depression and prolongs antinociception.". Anesthesiology 116 (1): 56–64. PMID 22082683. 
  30. ^ 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): 547–55. PMID 11591455. 
  31. ^ 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. PMID 16545572. 
  32. ^ Guenther, U; Theuerkauf, NU; Huse, D; Boettcher, MF; Wensing, G; Putensen, C; Hoeft, A (January 2012). "Selective 5-HT(1A)-R-agonist repinotan prevents remifentanil-induced ventilatory depression and prolongs antinociception.". Anesthesiology 116 (1): 56–64. PMID 22082683. 
  33. ^ 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): 119–20. PMID 15857296. 
  34. ^ 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. PMID 15733223.