Pharmacokinetics and metabolism of SRX246: A potent and selective vasopressin 1a antagonist

Journal of Pharmaceutical Sciences

Volumn 102, Issue 6, 2013, Pages 2033-2043

  Fabio, Karine M ^a   Guillon, Christophe D ^a,b   Lu, Shi fang ^a,b   Heindel, Ned D ^a   Brownstein, Michael J ^b   Lacey, Carl J ^a   Garippa, Carrie ^a   Simon, Neal G ^a,b  

^a LEHIGH UNIVERSITY   (United States)

^b Azevan Pharmaceuticals Inc   (United States)

Author keywords

Bioavailability; Clearance; Intermittent explosive disorder; Major depression; Metabolism; Permeability; Pharmacokinetics; PTSD; Serum protein binding; Vasopressin V1a receptor antagonist

Indexed keywords

SRX 246; UNCLASSIFIED DRUG; VASOPRESSIN ANTAGONIST;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; ARTIFICIAL MEMBRANE; BLOOD BRAIN BARRIER; DOG; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG HALF LIFE; DRUG METABOLISM; DRUG PENETRATION; DRUG PROTEIN BINDING; DRUG STABILITY; FEMALE; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; LIVER METABOLISM; MALE; MAXIMUM PLASMA CONCENTRATION; MEAN RESIDENCE TIME; NONHUMAN; RAT; TIME TO MAXIMUM PLASMA CONCENTRATION;

EID: 84877927696     PISSN: 00223549     EISSN: 15206017     Source Type: Journal    
DOI: 10.1002/jps.23495     Document Type: Article

References (28)

1. Goekoop JG, de Winter RP, de Rijk R, Zwinderman KH, Frankhuijzen-Sierevogel A, Wiegant VM. 2006. Depression with above-normal plasma vasopressin: Validation by relations with family history of depression and mixed anxiety and retardation. Psychiatry Res 141(2):201-211.
2. Keck ME. 2006. Corticotropin-releasing factor, vasopressin and receptor systems in depression and anxiety. Amino Acids 31(3):241-250.
3. Landgraf R. 2006. The involvement of the vasopressin system in stress-related disorders. CNS Neurol Disord Drug Targets 5:167-179.
4. Meynen G, Unmehopa UA, van Heerikhuize JJ, Hofman MA, Swaab DF, Hoogendijk WJ. 2006. Increased arginine vasopressin mRNA expression in the human hypothalamus in depression: A preliminary report. Biol Psychiatry 60:892-895.
5. Ring RH. 2005. The central vasopressinergic system: Examining the opportunities for psychiatric drug development. Curr Pharm Des 11:205-225.
6. Ryckmans T. 2010. Modulation of the vasopressin system for the treatment of CNS diseases. Curr Opin Drug Discov Devel 5:538-47.
7. Landgraf R, Wigger A. 2003. Born to be anxious: Neuroendocrine and genetic correlates of trait anxiety in HAB rats. Stress 6:111-119.
8. Keck ME, Welt T, Müller MB, Uhr M, Ohl M, Ohl F, Wigger A, Toschi N, Holsboer F, Landgraf R. 2003. Reduction of hypothalamic vasopressinergic hyperdrive contributes to clinically relevant behavioral and neuroendocrine effects of chronic paroxetine treatment in a psychopathological rat model. Neuropsychopharmacology 28(2):235-243.
9. Bunck M, Czibere L, Horvath C, Graf C, Frank E, Keßler MS, Murgatroyd C, Müller-Myhsok B, Gonik M, Weber P, Pütz B, Muigg P, Panhuysen M, Singewald N, Bettecken T, Deussing JM, Holsboer F, Spengler D, Landgraf R. 2009. A hypomorphic vasopressin allele prevents anxiety-related behavior. PLoS ONE 4(4):e5129.
10. Wigger A, Sánchez MM, Mathys, KC, Ebner K, Frank E, Liu D, Kresse A, Neumann ID, Holsboer F, Plotsky PM, Landgraf R. 2004. Alterations in central neuropeptide expression, release, and receptor binding in rats bred for high anxiety: Critical role of vasopressin. Neuropsychopharmacology 29(1):1-14.
11. Merali Z, Kent P, Du L, Hrdina P, Palkovits M, Faludi G, Poulter MO, Bédard T, Anisman H. 2006. Corticotropin-releasing hormone, arginine vasopressin, gastrin-releasing peptide, and neuromedin B alterations in stress-relevant brain regions of suicides and control subjects. Biol Psychiatry 59:594-602.
12. Purba JS, Hoogendijk WJ, Hofman MA, Swaab DF. 1996. Increased number of vasopressin- and oxytocin-expressing neurons in the paraventricular nucleus of the hypothalamus in depression. Arch Gen Psychiatry 53:137-143.
13. Ferris CF, Stolberg T, Kulkarni P, Murugavel M, Blanchard R, Blanchard CD, Febo1 M, Brevard M, Simon NG. 2008. Imaging the neural circuitry and chemical control of aggressive motivation. BMC Neurosci 9:111.
14. Ferris CF, Smerkers B, Simon NG. 2011. Blocking recall of conditioned fear in an animal model of PTSD with a V1a receptor antagonist. In 41st Annual Meeting of Society for Neuroscience; Washington, DC; November 12-16, 2011.
15. Guillon CD, Koppel GA, Brownstein MJ, Chaney MO, Ferris CF, Lu SF, Fabio KM, Miller MJ, Heindel ND, Hunden DC, Cooper RD, Kaldor SW, Dressman BA, Clay MP, Steinberg MI, Bruns RF, Simon NG 2007. Azetidinones as vasopressin V1a antagonists. Bioorg Med Chem 15(5):2054-2080.
16. Fabio K, Guillon C, Lu SF, Heindel ND, Miller M, Ferris CF, Brownstein MJ, Garripa C, Steiner M, Coccaro E, Damiano E, Koppel GA, Simon NG. 2010. Vasopressin antagonists as anxiolytics and antidepressants: Recent developments. Frontiers CNS Drug Discov 1:156-183.
17. Di L, Kerns E, Fan K, McConnell O, Carter G. 2003. High throughput artificial membrane permeability assay for blood-brain barrier. J Eur Med Chem 38(3):223-232.
18. Daniel S, Lynch J. Multiscreen® filter plates for PAMPA. Application note by Millipore®. Accessed, at: www.millipore.com. Last accessed on 02/26/2013.
19. Ruell JA, Avdeef A. 2004. Absorption screening using the PAMPA approach. In Methods in pharmacology and toxicology optimization in drug discovery: In vitro methods; Yan Z, Caldwell G, Eds. New York: Humana Press, pp 37-63.
20. Wohnsland F, Faller BJ. 2001. High-throughput permeability pH profile and high-throughput alkane/water log P with artificial membranes. J Med Chem 44(6):923-930.
21. Avdeef A, Bendels S, Di L, Faller B, Kansy M, Sugano K, Yamauchi Y. 2007. PAMPA-Critical factors for better predictions of absorption. J Pharm Sci 96(11):2893-2909.
22. Faller B. 2008. Artificial membrane assays to assess permeability. Curr Drug Metab 9:886-892.
23. Di L, Kerns E, Bezar I, Petusky S, Huang Y. 2009. Comparison of blood-brain barrier permeability assays: In situ brain perfusion, MDR1-MDCKII and PAMPA-BBB. J Pharm Sci 98(6):1980-1991.
24. Simon NG, Fabio K, Guillon C, Lu SF, Brownstein MJ, Ferris CF, Heindel ND. 2011. Novel vasopressin 1a antagonists for CNS disorders: Development and characterization of clinical candidates. In 41st Annual Meeting of Society for Neuroscience; Washington, DC; November 11-16, 2011.
25. Ferris CF, Lu SF, Messenger T, Guillon CD, Heindel ND, Miller MJ, Koppel GA, Robert Bruns F, Simon NG. 2006. Orally active vasopressin V1a receptor antagonist, SRX251, selectively blocks aggressive behavior. Pharmacol Biochem Behav 83(2):169-174.
26. Katritzky AR, Pozharskii AF. 2000. Handbook of heterocyclic chemistry, 2nd ed. New York: Pergamon Press, pp 56.
27. Simon, NG. 2012. A novel V1a receptor antagonist and potential antidepressant, SRX246, blocks vasopressin mediated effects on stress and fear: An fMRI study. In 52nd NCDEU Meeting; Phoenix, Arizona; May 29 to June 1, 2012.
28. Lee RJ, Coccaro EF, McCarron R, Towle VL, Lu SF, Guillon C, Fabio K, Brownstein M, Simon N. 2012. Vasopressinergic modulation of emotion: A pilot fMRI study. In 52nd NCDEU Meeting; Phoenix, Arizona; May 29-June 1, 2012.