setipiprant

Acting through DP₂, PGD₂ can inhibit hair growth, suggesting that this receptor is a potential target for bald treatment.{{cite journal | vauthors = 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 | title = Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia | journal = Science Translational Medicine | volume = 4 | issue = 126 | pages = 126ra34 | date = March 2012 | pmid = 22440736 | pmc = 3319975 | doi = 10.1126/scitranslmed.3003122 }} 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 and did not find statistically significant improvement.{{ClinicalTrialsGov|NCT02781311|Phase 2A Study of Setipiprant Tablets in Androgenetic Alopecia in Males}}

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.{{cite journal | vauthors = Norman P | title = Update on the status of DP2 receptor antagonists; from proof of concept through clinical failures to promising new drugs | journal = Expert Opinion on Investigational Drugs | volume = 23 | issue = 1 | pages = 55–66 | date = January 2014 | pmid = 24073896 | doi = 10.1517/13543784.2013.839658 | s2cid = 19977989 }}

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.{{cite journal | vauthors = Ratner P, Andrews CP, Hampel FC, Martin B, Mohar DE, Bourrelly D, Danaietash P, Mangialaio S, Dingemanse J, Hmissi A, van Bavel J | title = Efficacy and safety of setipiprant in seasonal allergic rhinitis: results from Phase 2 and Phase 3 randomized, double-blind, placebo- and active-referenced studies | journal = Allergy, Asthma, and Clinical Immunology | volume = 13 | pages = 18 | date = 2017 | pmid = 28392807 | pmc = 5379543 | doi = 10.1186/s13223-017-0183-z | doi-access = free }}

While setipiprant mildly induces the drug metabolizing enzyme CYP3A4 in vitro, the interaction appears to not be clinically relevant.{{cite journal | vauthors = Gehin M, Sidharta PN, Gnerre C, Treiber A, Halabi A, Dingemanse J | title = Pharmacokinetic interactions between simvastatin and setipiprant, a CRTH2 antagonist | journal = European Journal of Clinical Pharmacology | volume = 71 | issue = 1 | pages = 15–23 | date = January 2015 | pmid = 25323804 | doi = 10.1007/s00228-014-1767-x | s2cid = 17403672 }}

Setipiprant binds to the DP₂ receptor with a dissociation constant of 6 nM, representing potent antagonism of the receptor. 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. 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. 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.{{cite journal | vauthors = Fretz H, Valdenaire A, Pothier J, Hilpert K, Gnerre C, Peter O, Leroy X, Riederer MA | title = 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 = Journal of Medicinal Chemistry | volume = 56 | issue = 12 | pages = 4899–911 | date = June 2013 | pmid = 23721423 | doi = 10.1021/jm400122f }}

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

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

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.{{cite patent | inventor = Cotsarelis G, Fitzgerald G, Garza L |title= Compositions and methods for regulating hair growth | country = US | number = 20150072963 |url=http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20150072963.PGNR.&OS=DN/20150072963&RS=DN/20150072963 | assign1 = The Trustees of The University of Pennsylvania | pubdate = 12 March 2015 | postscript = . }}

The oral bioavailability of setipiprant is 44% in rats and 55% in dogs, which suggests that it should be orally bioavailable in humans. The half-life of setipiprant in humans is about 11 hours.{{cite journal | vauthors = Baldoni D, Mackie A, Gutierrez M, Theodor R, Dingemanse J | title = Setipiprant, a selective oral antagonist of human CRTH2: relative bioavailability of a capsule and a tablet formulation in healthy female and male subjects | journal = Clinical Therapeutics | volume = 35 | issue = 11 | pages = 1842–8 | date = November 2013 | pmid = 24095247 | doi = 10.1016/j.clinthera.2013.09.003 }} The maximum concentration in plasma (C_max) 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. C_max was reached between 1.8–4 hours after oral administration. The tablet and capsule formulations are bioequivalent.

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, but despite being well tolerated in clinical trials and showing reasonable efficacy against allergen-induced airway responses in asthmatic patients,{{cite journal | vauthors = Sidharta PN, Diamant Z, Dingemanse J | date = Dec 2014 | title = Single- and multiple-dose tolerability and pharmacokinetics of the CRTH2 antagonist setipiprant in healthy male subjects | journal = Fundam Clin Pharmacol | volume = 28 | issue = 6| pages = 690–9 | doi = 10.1111/fcp.12079 | pmid = 24734908 | s2cid = 8226504 }}{{cite journal | vauthors = Diamant Z, Sidharta PN, Singh D, O'Connor BJ, Zuiker R, Leaker BR, Silkey M, Dingemanse J | date = Aug 2014 | title = Setipiprant, a selective CRTH2 antagonist, reduces allergen-induced airway responses in allergic asthmatics | journal = Clin Exp Allergy | volume = 44 | issue = 8| pages = 1044–52 | doi = 10.1111/cea.12357 | pmid = 24964348 | s2cid = 5222512 }} it failed to show sufficient advantages over existing drugs and was discontinued from further development in this application.

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,{{cite journal | vauthors = 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 | display-authors = 6 | title = Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia | journal = Science Translational Medicine | volume = 4 | issue = 126 | pages = 126ra34 | date = March 2012 | pmid = 22440736 | pmc = 3319975 | doi = 10.1126/scitranslmed.3003122 }} the rights to setipiprant were acquired by Kythera to develop the drug as a novel treatment for baldness.{{cite patent | url = https://www.google.com/patents/US20150072963 | country = US | number = 20150072963 | inventor = Cotsarelis G, Fitzgerald G, Garza L | title = Compositions and methods for regulating hair growth. | assign1 = University of Pennsylvania | pubdate = 12 March 2015 | postscript = . }} 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.{{cite web | url = http://www.kythera.com/products/kyth-105-setipiprant/ | archive-url = https://web.archive.org/web/20150503224645/http://www.kythera.com/products/kyth-105-setipiprant/ | work = Pipeline | publisher = Kythera Biopharmaceuticals | title = KYTH-105 (setipiprant) | archive-date = 3 May 2015 }} {{As of|2015}}, setipiprant is currently under development by Allergan for the prevention of androgenic alopecia after their successful acquisition of Kythera.{{Cite web|url=https://www.allergan.com/news/news/thomson-reuters/allergan-successfully-completes-kythera-acquisitio| archive-url = https://web.archive.org/web/20151103234112/https://www.allergan.com/news/news/thomson-reuters/allergan-successfully-completes-kythera-acquisitio | archive-date = 3 November 2015 |title=Allergan Successfully Completes Kythera Acquisition| publisher = Allergan plc |date=2015}}

• Prostaglandin DP2 receptor
• Fevipiprant
• Ramatroban

{{Reflist|2}}

• [http://adisinsight.springer.com/drugs/800018368 Setipiprant - AdisInsight]

{{Other dermatological preparations}}

{{Prostanoid signaling modulators}}

Category:Prostaglandins

Category:Receptor antagonists

Category:1-Naphthyl compounds