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  • none
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Legal status
  • Investigational
  • 2-[8-Fluoro-2-(naphthalene-1-carbonyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-5-yl]acetic acid
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Molar mass402.425 g·mol−1
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  • c15ccccc5cccc1C(=O)N(CC3)Cc2c3n(CC(O)=O)c(cc4)c2cc4F
  • InChI=1S/C24H19FN2O3/c25-16-8-9-21-19(12-16)20-13-26(11-10-22(20)27(21)14-23(28)29)24(30)18-7-3-5-15-4-1-2-6-17(15)18/h1-9,12H,10-11,13-14H2,(H,28,29)

Setipiprant (INN; developmental code names ACT-129968, KYTH-105) is an investigational drug developed for the treatment of asthma and scalp hair loss. It was originally developed by Actelion and acts as a selective, orally available antagonist of the prostaglandin D2 receptor 2 (DP2). The drug is being developed as a novel treatment for male pattern baldness by Allergan.

Medical uses

Scalp hair loss

Acting through DP2, PGD2 can inhibit hair growth, suggesting that this receptor is a potential target for bald treatment.[1] A phase 2A study to evaluate the safety, tolerability, and efficacy of oral setipiprant relative to a placebo in 18- to 49-year-old males with androgenetic alopecia was completed in May 2018 but no results have been published.[2]

Allergic conditions

Setipiprant proved to be well tolerated and reasonably effective in reducing allergen-induced airway responses in asthmatic patient clinical trials. However, the drug, while supporting the concept that DP2 contributes to asthmatic disease, did not show sufficient advantage over existing drugs and was discontinued from further development for this application.[3]

Adverse effects

Data from phase II and III clinical trials did not detect any severe adverse effects to setipiprant. The authors were unable to identify any pattern of adverse effects that differ from placebo, including subjective reporting of symptoms and objective laboratory monitoring.[4]


While setipiprant mildly induces the drug metabolizing enzyme CYP3A4 in vitro, the interaction appears to not be clinically relevant.[5]


Mechanism of action

Allergic conditions

Setipiprant binds to the DP2 receptor with a dissociation constant of 6 nM, representing potent antagonism of the receptor.[3] The DP2 receptor, also called the CRTh2 receptor, is a G-protein-coupled receptor (GPCR) that is expressed on certain inflammatory cells, such as eosinophils, basophils, and certain lymphocytes.[6] For its mechanism of action in the treatment of allergic conditions, setipiprant's DP2 antagonism prevents the action of prostaglandin D2 (PGD2) on these receptors. The DP2 receptor mediates the activation of type 2 helper T (Th2) cells, eosinophils, and basophils in the lungs, which are white blood cells implicated in producing the inflammatory response the characterizes allergic conditions.[3] Activation of DP2 on Th2 cells by PGD2 induces the secretion of inflammatory cytokines (interleukin (IL) 4, IL-5, and IL-13), which cause an increase of eosinophils in the blood, remodeling of lung tissue, and hypersensitivity of lung tissue to allergens.[6]

Setipiprant does not antagonize the thromboxane receptor (TP).[6] The bronchoconstricting properties of PGD2 are not inhibited by setipiprant, since these are mediated by the TP receptor.[3] As a point of contrast, ramatroban is a selective TP antagonist and DP2 receptor antagonist.[3]

Setipiprant does not appreciably inhibit the activity of the enzyme cyclooxygenase 1 (COX-1), which is responsible for the synthesis of prostaglandins (including PGD2).[6]

Scalp hair loss

Prostaglandin D2 synthase (PTGDS) is an enzyme that produces PGD2. In men with androgenic alopecia, the enzyme PTGDS is elevated in the bald scalp tissue, as well as its product PGD2. PGD2 inhibits the growth of hair follicles through its activity on the DP2 receptor, but not the DP1 receptor. Theoretically, setipiprant's DP2 receptor antagonism may counteract the activity of PGD2 in hair follicles, thereby stimulating hair growth.[7]


The oral bioavailability of setipiprant is 44% in rats and 55% in dogs, which suggests that it should be orally bioavailable in humans.[6] The half life of setipiprant in humans is about 11 hours.[8] The maximum concentration in plasma (Cmax) is 6.04 and 6.44 mcg/mL for setipiprant tablets and capsules respectively, with an area under the curve of 31.88 and 31.50 mcg×hours/mL for setipiprant tablets and capsules respectively.[8] Cmax was reached between 1.8–4 hours after oral administration.[8] The tablet and capsule formulations are bioequivalent.[8]


Setipiprant appears as a light yellow to yellow colored solid. Based on general guidelines, the powder form is considered stable for 2 years at 4 degrees C, and for 3 years as -20 degrees C. When dissolved in a solvent, setipiprant is stable for 1 month at -20 degrees C, and 6 months at -80 degrees C. It is considered soluble in DMSO at concentrations ≥ 36 mg/mL.


Setipiprant was initially researched by Actelion as a treatment for allergies and inflammatory disorders, particularly asthma,[6] but despite being well tolerated in clinical trials and showing reasonable efficacy against allergen-induced airway responses in asthmatic patients,[9][10] it failed to show sufficient advantages over existing drugs and was discontinued from further development in this application.[3]

However, following the discovery in 2012 that the prostaglandin D2 receptor (DP/PGD2) is expressed at high levels in the scalp of men affected by male pattern baldness,[11] the rights to setipiprant were acquired by Kythera to develop the drug as a novel treatment for baldness.[12] The favorable pharmacokinetics and relative lack of side effects seen in earlier clinical trials mean that fresh clinical trials for this new application can be conducted fairly quickly.[13] As of 2015, setipiprant is currently under development by Allergan for the prevention of androgenic alopecia after their successful acquisition of Kythera.[14]

See also


  1. ^ Garza LA, Liu Y, Yang Z, Alagesan B, Lawson JA, Norberg SM, Loy DE, Zhao T, Blatt HB, Stanton DC, Carrasco L, Ahluwalia G, Fischer SM, FitzGerald GA, Cotsarelis G (March 2012). "Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia". Science Translational Medicine. 4 (126): 126ra34. doi:10.1126/scitranslmed.3003122. PMC 3319975. PMID 22440736.
  2. ^ "Phase 2A Study of Setipiprant Tablets in Androgenetic Alopecia in Males - Full Text View -". Retrieved 2018-04-21.
  3. ^ a b c d e f Norman P (January 2014). "Update on the status of DP2 receptor antagonists; from proof of concept through clinical failures to promising new drugs". Expert Opinion on Investigational Drugs. 23 (1): 55–66. doi:10.1517/13543784.2013.839658. PMID 24073896.
  4. ^ Ratner P, Andrews CP, Hampel FC, Martin B, Mohar DE, Bourrelly D, Danaietash P, Mangialaio S, Dingemanse J, Hmissi A, van Bavel J (2017). "Efficacy and safety of setipiprant in seasonal allergic rhinitis: results from Phase 2 and Phase 3 randomized, double-blind, placebo- and active-referenced studies". Allergy, Asthma, and Clinical Immunology. 13: 18. doi:10.1186/s13223-017-0183-z. PMC 5379543. PMID 28392807.
  5. ^ Gehin M, Sidharta PN, Gnerre C, Treiber A, Halabi A, Dingemanse J (January 2015). "Pharmacokinetic interactions between simvastatin and setipiprant, a CRTH2 antagonist". European Journal of Clinical Pharmacology. 71 (1): 15–23. doi:10.1007/s00228-014-1767-x. PMID 25323804.
  6. ^ a b c d e f Fretz H, Valdenaire A, Pothier J, Hilpert K, Gnerre C, Peter O, Leroy X, Riederer MA (June 2013). "Identification of 2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (setipiprant/ACT-129968), a potent, selective, and orally bioavailable chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonist". Journal of Medicinal Chemistry. 56 (12): 4899–911. doi:10.1021/jm400122f. PMID 23721423.
  7. ^ Cotsarelis, George; Fitzgerald, Garret; Garza, Luis (12 March 2015). "United States Patent Application: 0150072963 - COMPOSITIONS AND METHODS FOR REGULATING HAIR GROWTH". US Patent & Trademark Office. Retrieved 19 May 2018.
  8. ^ a b c d Baldoni D, Mackie A, Gutierrez M, Theodor R, Dingemanse J (November 2013). "Setipiprant, a selective oral antagonist of human CRTH2: relative bioavailability of a capsule and a tablet formulation in healthy female and male subjects". Clinical Therapeutics. 35 (11): 1842–8. doi:10.1016/j.clinthera.2013.09.003. PMID 24095247.
  9. ^ Sidharta PN, Diamant Z, Dingemanse J (Dec 2014). "Single- and multiple-dose tolerability and pharmacokinetics of the CRTH2 antagonist setipiprant in healthy male subjects". Fundam Clin Pharmacol. 28 (6): 690–9. doi:10.1111/fcp.12079. PMID 24734908.
  10. ^ Diamant Z, Sidharta PN, Singh D, O'Connor BJ, Zuiker R, Leaker BR, Silkey M, Dingemanse J (Aug 2014). "Setipiprant, a selective CRTH2 antagonist, reduces allergen-induced airway responses in allergic asthmatics". Clin Exp Allergy. 44 (8): 1044–52. doi:10.1111/cea.12357. PMID 24964348.
  11. ^ Garza LA, et al. (2012). "Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia". Science Translational Medicine. 4 (126): 126–34. doi:10.1126/scitranslmed.3003122. PMC 3319975. PMID 22440736.
  12. ^ George Cotsarelis, Garret Fitzgerald, Luis Garza. Compositions and methods for regulating hair growth. US Patent application 2015/0072963
  13. ^ Pipeline KYTH-105 (setipiprant)
  14. ^ "Allergan Successfully Completes Kythera Acquisition". 2015.

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