Description
Setipiprant is an orally bioavailable antagonist of the prostaglandin D2 (PGD2) receptor CRTH2/DP2 (IC50 = 6 nM for the human receptor). It is selective for CRTH2/DP2 over DP1 in a radioligand binding assay (IC50 = 1,290 nM) and the prostaglandin E2 (PGE2) receptor subtypes EP2 and EP4 in a β-arrestin assay (IC50s = 2,600 and >10,000 nM, respectively). Setipiprant inhibits PGD2-induced calcium flux in HEK293 cells expressing human CRTH2/DP2 (IC50 = 30 nM) and PGD2-induced shape change in human eosinophils (IC50 = 235 nM).
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.
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.
Indications
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.
Definition
ChEBI: Setipiprant is a naphthalenecarboxamide.
Biological Activity
A potent and selective CRTh2 antagonist. CRTh2 is a G-protein-coupled receptor for prostaglandin D2 (PGD2), a key mediator in inflammatory disorders.
Mechanism of action
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.
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).
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.
Pharmacokinetics
The oal hicalailityof setipiorartis44% in rts and % in dog, wichsugestistht itshoud beoall ioalale in humanst . theha ltfscf setprnt in humans is bot 11 hours.The
maximum concentration in plasma(Cmax is 6.04 and 6.44 mcgrml for setipiprant tablets and capule respectively with an area under the curve of 31.88 and 31.5l mcg hours/ml for setipiprantbles.
and capsules respectively.8BCmay was reached between 1.8-4 hours after oral administration.8.The tablet and capsul formulations are bioequivalent.
Side 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.
