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Bremelanotide

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Bremelanotide
Clinical data
ATC code
  • None
Legal status
Legal status
  • US: Unscheduled
Pharmacokinetic data
Elimination half-life120 minutes[1]
Identifiers
  • (3S,6S,9R,12S,15S,23S)-15-[(N-Acetyl-L-norleucyl)amino]-9-benzyl-6-{3-[(diaminomethylidene)amino]propyl}-12-(1H-imidazol-5-ylmethyl)-3-(1H-indol-3-ylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexaazacyclotricosane-23-carboxylic acid
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC50H68N14O10
Molar mass1025.2 g/mol g·mol−1
3D model (JSmol)
  • O=C(C)N[C@@H](CCCC)C(N[C@@H]1C(N[C@@H](CC2=CNC=N2)C(N[C@H](CC3=CC=CC=C3)C(N[C@@H](CCC/N=C(N)\N)C(N[C@@H](CC4=CNC5C=CC=CC45)C(N[C@@H](CCCCNC(C1)=O)C(O)=O)=O)=O)=O)=O)=O)=O
  • InChI=1S/C50H68N14O10/c1-3-4-16-35(58-29(2)65)43(67)64-41-25-42(66)54-20-11-10-18-37(49(73)74)60-46(70)39(23-31-26-56-34-17-9-8-15-33(31)34)62-44(68)36(19-12-21-55-50(51)52)59-45(69)38(22-30-13-6-5-7-14-30)61-47(71)40(63-48(41)72)24-32-27-53-28-57-32/h5-9,13-15,17,26-28,35-41,56H,3-4,10-12,16,18-25H2,1-2H3,(H,53,57)(H,54,66)(H,58,65)(H,59,69)(H,60,70)(H,61,71)(H,62,68)(H,63,72)(H,64,67)(H,73,74)(H4,51,52,55)/t35-,36-,37-,38+,39-,40-,41-/m0/s1 checkY
  • Key:FFHBJDQSGDNCIV-MFVUMRCOSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Bremelanotide (/ˌbrɛm[invalid input: 'ɨ']ˈlænətaɪd/ ⓘ) INN, USAN), formerly known as PT-141, is a peptide drug which has been under development by Palatin Technologies as a treatment for female sexual dysfunction (FSD), hemorrhagic shock, and reperfusion injury. Bremelanotide was originally tested for intranasal administration in treating FSD but this application was temporarily discontinued in 2008 after concerns were raised over increased blood pressure seen with bremelanotide administration in some patients. As of December 2014, Palatin is conducting a human phase III study[2] using a subcutaneous drug delivery system that appears to have little effect on blood pressure.

Positive results of bremelanotide in the treatment of hypoactive sexual desire disorder (HSDD) in two late-stage phase III clinical trials were announced by Palatin on 1 November 2016.[3] The company is expected to seek approval of bremelanotide for this indication in the United States in the second half of 2017.[3]

Clinical development

Bremelanotide was developed from the peptide hormone melanotan II which underwent testing as a sunless tanning agent. In initial testing, melanotan II did induce the production of darkening dermal pigmentation (melanogenesis) but additionally caused sexual arousal and spontaneous erections as unexpected side effects in nine out of the ten original male volunteer test subjects.[4]

In studies, bremelanotide was shown to induce lordosis in an animal model[5] and was also effective in treating sexual dysfunction in both men (erectile dysfunction or impotence) and women (sexual arousal disorder). Unlike sildenafil (Viagra) and other related medications, it does not act upon the vascular system, but directly increases sexual desire via acting in the brain.[6]

A phase III clinical trial was scheduled to begin in the first half of 2007, but was delayed until August 2007. On August 30, Palatin announced that the U.S. Food and Drug Administration had expressed serious concerns regarding the risk/benefit ratio of bremelanotide with regards to the side effect of increased blood pressure. The FDA stated that it would consider alternate uses for bremelanotide, including as a treatment for individuals who do not respond to more established ED treatments. However, on May 13, 2008, Palatin Technologies announced it had "discontinued development of bremelanotide for the treatment of male and female sexual dysfunction" while concurrently announcing plans to develop it as a treatment for hemorrhagic shock instead.[7] The company additionally announced intentions to focus its attention on another, more selective compound, PL-6983, that was found to produce lower increases in blood pressure in animal models.[8] Palatin has since re-initiated bremelanotide studies for ED and FSD using a subcutaneous delivery method. On August 12, 2009, the company announced that in a double-blind study of 54 volunteers bremelanotide failed to evoke the hypertensive side effects seen with the nasal delivery system used in prior studies, concluding that "variability of uptake" inherent in intranasal administration of the drug resulted in "increases in blood pressure and gastrointestinal events...primarily related to high plasma levels in [only] a subset of patients" and that subcutaneous administration of the drug circumvented the potential for this side effect.[9] Palatin has completed a human phase IIb study utilizing subcutaneous administration and reported positive results.[10]

In Australia, Bremelanotide is being studied to treat Autism in males between the ages of 16-65. The Phase 2 study is sponsored by the University of Sydney and is titled "A Within-Subject Single Dose Trial on the Effects of Bremelanotide on Social Cognition and Behaviour"[11]

Bremelanotide, via the subcutaneous injection route, has been studied in human clinical trials in doses of 0.75, 1.25, and 1.75 mg, with its effectiveness in treating sexual dysfunction increasing with each dosage and side effect rates remaining similar.[12]

Pharmacology

Bremelanotide, similarly to its analogues α-MSH and melanotan II, acts as a non-selective agonist of all of the melanocortin receptors except MC2, where it lacks significant affinity.[13] Reported activity of the drug is as follows:[14]

  • MC1 (Ki = 0.68 nM)
  • MC2 (Ki > 1000 nM)
  • MC3 (Ki = 72.07 nM)
  • MC4 (Ki = 19.25 nM)
  • MC5 (Ki = 166.8 nM)

Bremelanotide appears to stimulate sexual desire and arousal completely or mostly via activation of the MC4 receptor (the MC3 receptor may also be involved).[1] It modulates inflammation and limits ischemia via activation of the MC1 and MC4 receptors.[15]

According to Palatin Technologies' original 2003 patent for bremelanotide, it possesses approximately 50 times the potency of melanotan II as an inducer of erection in male rats.[16] In addition, it was stated in the patent that the therapeutic window of bremelanotide in animals (specifically, the range of induction of the desired sexual arousal relative to the induction of side effects including nausea, yawning, stretching, and decreased appetite) was >1,000-fold, whereas that of melanotan II was only 3- to 4-fold.[16] They concluded that bremelanotide would be more tolerable than melanotan II.[16] However, in human clinical trials, bremelanotide has, similarly to melanotan II, been found to produce nausea and vomiting (though yawning, stretching, and loss of appetite do not seem to have been reported).[17][18] Other side effects reported for bremelanotide in human clinical trials include transient facial flushing, sweating, somnolence, headache, dizziness, dysgeusia (altered sense of taste), hypertension, and skin hyperpigmentation.[17][18][19]

Chemistry

Bremelanotide is a cyclic heptapeptide lactam analog of α-melanocyte-stimulating hormone (α-MSH). It has the amino acid sequence Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH, and is also known as cyclo-[Nle4,Asp5,D-Phe7,Lys10]α-MSH-(4-10). Bremelanotide is an active metabolite of melanotan II that lacks the C-terminal amide group.

See also

References

  1. ^ a b King SH, Mayorov AV, Balse-Srinivasan P, Hruby VJ, Vanderah TW, Wessells H (2007). "Melanocortin receptors, melanotropic peptides and penile erection". Curr Top Med Chem. 7 (11): 1098–1106. doi:10.2174/1568026610707011111. PMC 2694735. PMID 17584130.
  2. ^ "Palatin Announces Start of Bremelanotide Phase 3 Program For Female Sexual Dysfunction". PR Newswire. Retrieved 2015-02-17.
  3. ^ a b http://www.techtimes.com/articles/184519/20161101/palatin-drug-that-boosts-sexual-desire-in-women-succeeds-in-trials.htm
  4. ^ "Tanning drug may find new life as Viagra alternative". CNN. 1999. Retrieved 2007-09-16.
  5. ^ Pfaus JG, Shadiack A, Van Soest T, Tse M, Molinoff P (July 2004). "Selective facilitation of sexual solicitation in the female rat by a melanocortin receptor agonist". Proc. Natl. Acad. Sci. U.S.A. 101 (27): 10201–4. Bibcode:2004PNAS..10110201P. doi:10.1073/pnas.0400491101. PMC 454387. PMID 15226502.
  6. ^ Vicki Mabrey (2006). "ABC News "The Business of Desire - Love Potion"". ABC News. Retrieved 2009-01-24.
  7. ^ "Palatin Technologies announces new strategic objectives and reports third quarter 2008 financial results". Palatin Technologies press release. 2008. Retrieved 2008-08-21.
  8. ^ "Palatin Technologies Announces New Strategic Objectives". Retrieved 2008-05-13.
  9. ^ "Palatin Technologies, Inc. reports positive bremelanotide study; improved safety profile with subcutaneous administration". Retrieved 2009-08-12.
  10. ^ "Palatin Technologies reports positive results for Phase 2B Bremelanotide Female Sexual Dysfunction Trial". www.palatin.com. Retrieved 20 January 2016.
  11. ^ "Trial registered on ANZCTR".
  12. ^ "Archived copy" (PDF). Archived from the original (PDF) on 2009-02-03. Retrieved 2009-01-19. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)CS1 maint: archived copy as title (link)
  13. ^ Rossler, A; Pfaus, J; Kia, H; Bernabe, J; Alexandre, L; Giuliano, F (2006). "The melanocortin agonist, melanotan II, enhances proceptive sexual behaviors in the female rat". Pharmacology Biochemistry and Behavior. 85 (3): 514–521. doi:10.1016/j.pbb.2006.09.023. ISSN 0091-3057.
  14. ^ EP patent 1196184, Joanna K. Bernstein; Christine H. Blood & Guy W. Herbert et al., "Compositions for treatment of sexual dysfunction", published 2005-04-20, assigned to Palatin Technologies, Inc. 
  15. ^ Bremelanotide for Organ Protection and Related Indications Archived February 3, 2009, at the Wayback Machine, Palatin Technologies fact sheet. Retrieved on 2009-01-18.
  16. ^ a b c US patent 6579968, Christine H. Blood; Annette M. Shadiack & Joanna K. Bernstein et al., "Compositions and methods for treatment of sexual dysfunction", published 17 June 2003, assigned to Palatin Technologies, Inc. 
  17. ^ a b Safarinejad, Mohammad Reza; Hosseini, Seyyed Yousof (2008). "Salvage of Sildenafil Failures With Bremelanotide: A Randomized, Double-Blind, Placebo Controlled Study". The Journal of Urology. 179 (3): 1066–1071. doi:10.1016/j.juro.2007.10.063. ISSN 0022-5347. PMID 18206919.
  18. ^ a b Safarinejad, Mohammad Reza (2008). "Evaluation of the Safety and Efficacy of Bremelanotide, a Melanocortin Receptor Agonist, in Female Subjects with Arousal Disorder: A Double-Blind Placebo-Controlled, Fixed Dose, Randomized Study". The Journal of Sexual Medicine. 5 (4): 887–897. doi:10.1111/j.1743-6109.2007.00698.x. ISSN 1743-6095. PMID 18179455.
  19. ^ "Archived copy" (PDF). Archived from the original (PDF) on 2016-03-04. Retrieved 2015-07-12. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)CS1 maint: archived copy as title (link)
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