Prostaglandin D2
Prostaglandin D2 (or PGD2) is a prostaglandin that binds to the receptor PTGDR, as well as CRTH2. It is a major prostaglandin produced by mast cells. In mammalian organs, large amounts of PGD2 are found only in the brain and in mast cells. It is critical to development of allergic diseases such as asthma.
Research carried out in 1989 found PGD2 is the primary mediator of vasodilation (the "niacin flush") after ingestion of niacin (nicotinic acid).
A team of scientists working at the University of Pennsylvania have discovered PGD2 plays a significant role in typical MPB hair loss as well. The 2012 research paper indicates a causal link between elevated levels of localized prostaglandin D2 and hair loss. Applied topically, the research found PGD2 prevents hair growth, and mice that were genetically inclined to produce higher levels of PGD2 had inhibited hair growth. The research also found PGD2 levels were much higher in balding scalp tissue than nonbalding scalp tissue. The paper suggested one of the receptors involved in production of PGD2, GPR44, would therefore be a therapeutic targets for androgenic alopecia in both men and women with hair loss and thinning.
Because PGD2's relation to asthma has been known for several years, several drugs that seek to reduce PGD2 levels through blocking the GPR44 level are already in clinical trials.
A very important study that may lead to a future cure:
Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia.
Testosterone is necessary for the development of male pattern baldness, known as androgenetic alopecia (AGA); yet, the mechanisms for decreased hair growth in this disorder are unclear. We show that prostaglandin D(2) synthase (PTGDS) is elevated at the mRNA and protein levels in bald scalp compared to haired scalp of men with AGA. The product of PTGDS enzyme activity, prostaglandin D(2) (PGD(2)), is similarly elevated in bald scalp. During normal follicle cycling in mice, Ptgds and PGD(2) levels increase immediately preceding the regression phase, suggesting an inhibitory effect on hair growth. We show that PGD(2) inhibits hair growth in explanted human hair follicles and when applied topically to mice. Hair growth inhibition requires the PGD(2) receptor G protein (heterotrimeric guanine nucleotide)-coupled receptor 44 (GPR44), but not the PGD(2) receptor 1 (PTGDR). Furthermore, we find that a transgenic mouse, K14-Ptgs2, which targets prostaglandin-endoperoxide synthase 2 expression to the skin, demonstrates elevated levels of PGD(2) in the skin and develops alopecia, follicular miniaturization, and sebaceous gland hyperplasia, which are all hallmarks of human AGA. These results define PGD(2) as an inhibitor of hair growth in AGA and suggest the PGD(2)-GPR44 pathway as a potential target for treatment.
Clinical Studies
| Clinical Studies | Abstract |
| Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia. | Testosterone is necessary for the development of male pattern baldness, known as androgenetic alopecia (AGA); yet, the mechanisms for decreased hair growth in this disorder are unclear. We show that prostaglandin D(2) synthase (PTGDS) is elevated at the mRNA and protein levels in bald scalp compared to haired scalp of men with AGA. The product of PTGDS enzyme activity, prostaglandin D(2) (PGD(2)), is similarly elevated in bald scalp. During normal follicle cycling in mice, Ptgds and PGD(2) levels increase immediately preceding the regression phase, suggesting an inhibitory effect on hair growth. We show that PGD(2) inhibits hair growth in explanted human hair follicles and when applied topically to mice. Hair growth inhibition requires the PGD(2) receptor G protein (heterotrimeric guanine nucleotide)-coupled receptor 44 (GPR44), but not the PGD(2) receptor 1 (PTGDR). Furthermore, we find that a transgenic mouse, K14-Ptgs2, which targets prostaglandin-endoperoxide synthase 2 expression to the skin, demonstrates elevated levels of PGD(2) in the skin and develops alopecia, follicular miniaturization, and sebaceous gland hyperplasia, which are all hallmarks of human AGA. These results define PGD(2) as an inhibitor of hair growth in AGA and suggest the PGD(2)-GPR44 pathway as a potential target for treatment. |
| Antagonists of the prostaglandin D2 receptor CRTH2 | Prostaglandin D(2) (PGD(2)) is produced by mast cells, Th2 lymphocytes and dendritic cells and causes activation of Th2 lymphocytes, eosinophils and basophils through a high-affinity interaction with the G protein-coupled receptor chemoattractant homologous receptor expressed on Th2 cells (CRTH2, also known as DP(2)). Activation of CRTH2 induces chemotaxis of Th2 lymphocytes and eosinophils and has the unusual property of promoting cytokine production by Th2 lymphocytes in the absence of allergen or co-stimulation. The ability of supernatants from immunologically activated mast cells to activate Th2 cells and eosinophils is mediated by CRTH2. This receptor also plays an important role in amplifying allergic responses through paracrine activation of Th2 cells. Pharmacological blockade or genetic ablation of CRTH2 is associated with a reduction in airways inflammation and reduced levels of mucus, Th2 cytokines and immunoglobulin E. The central role played by CRTH2 in mediating these effects suggests that antagonism of this receptor is an attractive approach to the treatment of chronic allergic disease. |
| On the mechanism of interaction of potent surmountable and insurmountable antagonists with the prostaglandin D2 receptor CRTH2. | Chemoattractant receptor-homologous molecule expressed on T helper 2 cells (CRTH2) has attracted interest as a potential therapeutic target in inflammatory diseases. Ramatroban, a thromboxane A2 receptor antagonist with clinical efficacy in allergic rhinitis, was recently found to also display potent CRTH2 antagonistic activity. Here, we present the pharmacological profile of three ramatroban analogs that differ chemically from ramatroban by either a single additional methyl group (TM30642), or an acetic acid instead of a propionic acid side chain (TM30643), or both modifications (TM30089). All three compounds bound to human CRTH2 stably expressed in human embryonic kidney 293 cells with nanomolar affinity. [3H]Prostaglandin D2 (PGD2) saturation analysis reveals that ramatroban and TM30642 decrease PGD2 affinity, whereas TM30643 and TM30089 exclusively depress ligand binding capacity (Bmax). Each of the three compounds acted as potent CRTH2 antagonists, yet the nature of their antagonism differed markedly. In functional assays measuring inhibition of PGD2-mediated 1) guanosine 5'-O-(3-thio)triphosphate binding, 2) beta-arrestin translocation, and 3) shape change of human eosinophils endogenously expressing CRTH2, ramatroban, and TM30642 produced surmountable antagonism and parallel rightward shifts of the PGD2 concentration-response curves. For TM30643 and TM30089, this shift was accompanied by a progressive reduction of maximal response. Binding analyses indicated that the functional insurmountability of TM30643 and TM30089 was probably related to long-lasting CRTH2 inhibition mediated via the orthosteric site of the receptor. A mechanistic understanding of insurmountability of CRTH2 antagonists could be fundamental for development of this novel class of anti-inflammatory drugs. |
| Indole-3-acetic acid antagonists of the prostaglandin D2 receptor CRTH2 | Prostaglandin D2 (PGD2) acting at the CRTH2 receptor (chemoattractant receptor-homologous molecule expressed on Th2 cells) has been linked with a variety of allergic and other inflammatory diseases. We describe a family of indole-1-sulfonyl-3-acetic acids that are potent and selective CRTH2 antagonists that possess good oral bioavailability. The compounds may serve as novel starting points for the development of treatments of inflammatory disease such as asthma, allergic rhinitis, and atopic dermatitis. |
| Diazine indole acetic acids as potent, selective, and orally bioavailable antagonists of chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2) for the treatment of allergic inflammatory diseases. | New classes of CRTH2 antagonists, the pyridazine linker containing indole acetic acids, are described. The initial hit 1 had good potency but poor permeability, metabolic stability, and PK. Initial optimization led to compounds of type 2 with low oxidative metabolism but poor oral bioavailability. Poor permeability was identified as a liability for these compounds. Addition of a linker between the indole and diazine moieties afforded a series with good potency, low rates of metabolism, moderate permeability, and good oral bioavailability in rodents. 32 was identified as the development track candidate. It was potent in cell based, binding, and whole blood assays and exhibited good PK profile. It was efficacious in mouse models of contact hypersensitivity (1 mg/kg b.i.d.) and house dust (20 mg/kg q.d.) when dosed orally. In sheep asthma, administration at 1 mg/kg iv completely blocked the LAR and AHR and attenuated the EAR phase. |
| Isoquinoline derivatives as potent CRTH2 receptor antagonists: synthesis and SAR. | Synthesis and structure-activity relationship of a novel series of isoquinoline CRTH2 receptor antagonists are described. One of the most potent compounds, TASP0376377 (6m), showed not only potent binding affinity (IC(50)=19 nM) but also excellent functional antagonist activity (IC(50)=13 nM). TASP0376377 was tested for its ability of a chemotaxis assay to show the effectiveness (IC(50)=23 nM), which was in good agreement with the CRTH2 antagonist potency. Furthermore, TASP0376377 showed sufficient selectivity for binding to CRTH2 over the DP1 prostanoid receptor (IC(50)>1 μM) and COX-1 and COX-2 enzymes (IC(50)>10 μM). |
| Optimization of phenylacetic acid derivatives for balanced CRTH2 and DP dual antagonists. | Our first generation CRTH2 and DP dual antagonists, represented by AMG 009, are more potent toward the CRTH2 receptor than to the DP receptor. Here we report our efforts in the discovery of CRTH2 and DP dual antagonists with more balanced potencies to both receptors, such as compound 15. |
| Discovery of novel and potent CRTH2 antagonists. | High throughput screening of our chemical library for CRTH2 antagonists provided a lead compound 1a. Initial optimization of the lead led to the discovery of a novel, potent and orally bioavailable CRTH2 antagonist 17 |
| Novel CRTH2 antagonists: a review of patents from 2006 to 2009. | IMPORTANCE OF THE FIELD: The receptor CRTH2 (also known as DP₂) is an important mediator of the inflammatory effects of prostaglandin D₂ and has attracted much attention as a therapeutic target for the treatment of conditions such as asthma, COPD, allergic rhinitis and atopic dermatitis. AREAS COVERED IN THIS REVIEW: The validation of CRTH2 as a therapeutic target and the early antagonists are summarized, CRTH2 antagonists published in the patent literature from 2006 to 2009 are comprehensively covered and a general update on the recent progress in the development of CRTH2 antagonists for the treatment of inflammatory diseases is provided. WHAT THE READER WILL GAIN: Insight into the validation of CRTH2 as a therapeutic target, a comprehensive overview of the development of new CRTH2 ligands between 2006 and 2009, and a general overview of the state of the art. TAKE HOME MESSAGE: Many diverse potent CRTH2 antagonists are now available, and several are in or on the way into the clinic. It is still early to draw final conclusions, but preliminary results give reason for optimism, and the prospect that we will see new CRTH2 antagonists reaching the market for the treatment of asthma, rhinitis, atopic dermatitis and/or COPD seems good. |
| PGD synthase and PGD2 in immune resposne. | PGD(2) is formed from arachidonic acid by successive enzyme reactions: oxygenation of arachidonic acid to PGH(2), a common precursor of various prostanoids, catalyzed by cyclooxygenase, and isomerization of PGH(2) to PGD(2) by PGD synthases (PGDSs). PGD(2) can be either pro- or anti-inflammatory depending on disease process and etiology. The anti-inflammatory and immunomodulatory attributes of PGDS/PGD(2) provide opportunities for development of novel therapeutic approaches for resistant infections and refractory inflammatory diseases. This paper highlights the role of PGD synthases and PGD2 in immune inflammatory response. |
| Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459. | CRTH2 is a G protein-coupled receptor expressed by Th2 lymphocytes and eosinophils that mediates prostaglandin D2 (PGD2) driven chemotaxis. We studied the efficacy of the oral CRTH2 antagonist OC000459 in steroid naive asthmatic patients.A randomised, double-blind, placebo-controlled, two-way crossover study of 16 days treatment with OC000459 (200 mg twice·day(-1)) on the late (LAR) and early (EAR) asthmatic responses to bronchial allergen challenge was conducted, with 16 subjects completing the study.There was a 25.4% reduction in the LAR area under the curve (AUC) for change in FEV1 with OC000459 compared to placebo (95% CI 5.1-45.6, p=0.018), but no effect on the EAR. Sputum eosinophil counts at 1 day post allergen challenge were lower after OC000459 treatment (p=0.002). PGD2 induced blood eosinophil shape change ex-vivo was assessed at day 7 (n=7). The AUC of eosinophil shift for OC000459 was lower than placebo; the mean difference was -33.6% (95% CI -66.8 to -0.4, p=0.048).OC000459 treatment inhibited the LAR and the post allergen increase in sputum eosinophils. This CRTH2 antagonist appears to inhibit allergic inflammation in asthma. |