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| Routes of administration | Oral |
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| Formula | C24H19FN2O3 |
| Molar mass | 402.425 g·mol−1 |
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Setipiprant (INN; developmental code namesACT-129968,KYTH-105) is aninvestigationaldrug developed for the treatment of asthma and scalp hair loss. It was originally developed byActelion and acts as a selective, orally availableantagonist of theprostaglandin D2 receptor 2 (DP2). The drug is being developed as a novel treatment for male pattern baldness byAllergan.
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 aplacebo in 18- to 49-year-old males with androgeneticalopecia was completed in May 2018 and did not find statistically significant improvement.[2]
Setipiprant proved to be well tolerated and reasonably effective in reducing allergen-induced airway responses in asthmatic patientclinical 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]
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 enzymeCYP3A4in vitro, the interaction appears to not be clinically relevant.[5]
Setipiprant binds to the DP2 receptor with adissociation constant of 6 nM, representing potent antagonism of the receptor.[3] The DP2 receptor, also called the CRTh2 receptor, is aG-protein-coupled receptor (GPCR) that is expressed on certain inflammatory cells, such aseosinophils,basophils, and certainlymphocytes.[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 oftype 2 helper T (Th2) cells, eosinophils, and basophils in the lungs, which arewhite 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 inflammatorycytokines (interleukin (IL) 4,IL-5, andIL-13), which causean increase of eosinophils in the blood, remodeling of lung tissue, and hypersensitivity of lung tissue toallergens.[6]
Setipiprant does not antagonize thethromboxane 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 enzymecyclooxygenase 1 (COX-1), which is responsible for the synthesis of prostaglandins (including PGD2).[6]
Prostaglandin D2 synthase (PTGDS) is an enzyme that produces PGD2. In men withandrogenic 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 oralbioavailability of setipiprant is 44% in rats and 55% in dogs, which suggests that it should be orally bioavailable in humans.[6] Thehalf-life of setipiprant in humans is about 11 hours.[8] Themaximum concentration in plasma (Cmax) is 6.04 and 6.44 mcg/mL for setipiprant tablets and capsules respectively, with anarea 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 inDMSO at concentrations ≥ 36 mg/mL.
Setipiprant was initially researched byActelion as a treatment for allergies and inflammatory disorders, particularlyasthma,[6] but despite being well tolerated inclinical 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 theprostaglandin D2 receptor (DP/PGD2) is expressed at high levels in the scalp of men affected bymale 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[update], setipiprant is currently under development byAllergan for the prevention of androgenic alopecia after their successful acquisition of Kythera.[14]
