Immunological activation of mast cells is an important trigger in the cascade of inflammatory events leading to the manifestation of allergic diseases. Pharmacological studies using the recently discovered DP(1) and CRTH2 antagonists combined with genetic analysis support the view that these receptors have a pivotal role in mediating aspects of allergic diseases that are resistant to current therapy. This Review focuses on the emerging roles that DP(1) and CRTH2 (also known as DP(2)) have in acute and chronic aspects of allergic diseases and proposes that, rather than having opposing actions, these receptors have complementary roles in the initiation and maintenance of the allergy state. We also discuss recent progress in the discovery and development of selective antagonists of these receptors.

D prostanoid receptor 2 (DP 2 ) [also known as chemoattractant receptor-homologous molecule expressed on T helper 2 (Th2) cells (CRTH2)] is selectively expressed by Th2 lymphocytes, eosinophils, and basophils and mediates recruitment and activation of these cell types in response to prostaglandin D 2 (PGD 2 ). (5-Fluoro-2-methyl-3-quinolin-2-ylmethylindo-1-yl)-acetic acid (OC000459) is an indole-acetic acid derivative that potently displaces [ 3 H]PGD 2 from human recombinant DP 2 (K i ϭ 0.013 M), rat recombinant DP 2 (K i ϭ 0.003 M), and human native DP 2 (Th2 cell membranes; K i ϭ 0.004 M) but does not interfere with the ligand binding properties or functional activities of other prostanoid receptors (prostaglandin E 1-4 receptors, D prostanoid receptor 1, thromboxane receptor, prostacyclin receptor, and prostaglandin F receptor). OC000459 inhibited chemotaxis (IC 50 ϭ 0.028 M) of human Th2 lymphocytes and cytokine production (IC 50 ϭ 0.019 M) by human Th2 lymphocytes. OC000459 competitively antagonized eosinophil shape change responses induced by PGD 2 in both isolated human leukocytes (pK B ϭ 7.9) and human whole blood (pK B ϭ 7.5) but did not inhibit responses to eotaxin, 5-oxo-eicosatetraenoic acid, or complement component C5a. OC000459 also inhibited the activation of Th2 cells and eosinophils in response to supernatants from IgE/anti-IgE-activated human mast cells. OC000459 had no significant inhibitory activity on a battery of 69 receptors and 19 enzymes including cyclooxygenase 1 (COX1) and COX2. OC000459 was found to be orally bioavailable in rats and effective in inhibiting blood eosinophilia induced by 13,14-dihydro-15-keto-PGD 2 (DK-PGD 2 ) in this species (ED 50 ϭ 0.04 mg/kg p.o.) and airway eosinophilia in response to an aerosol of DK-PGD 2 in guinea pigs (ED 50 ϭ 0.01 mg/kg p.o.). These data indicate that OC000459 is a potent, selective, and orally active DP 2 antagonist that retains activity in human whole blood and inhibits mast cell-dependent activation of both human Th2 lymphocytes and eosinophils.

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.

Gonadotropin-releasing hormone (GnRH) or luteinizing hormone-releasing hormone (LHRH) is a decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) hypothalamic hormone that acts upon 7-trans membrane spanning GnRH receptors in the pituitary. This action leads to the secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) that in turn act on the reproductive organs regulating gonadal steroid production, spermatogenesis and follicular development. Peptidic agonists of the GnRH receptor have been known for many years and are currently employed therapeutically in the treatment of prostate and breast tumours, uterine fibroids, precocious puberty, endometriosis, premenstrual syndrome, contraception and infertility. Peptidic antagonists to date have only been employed commercially in the treatment of infertility during assisted reproductive therapy; however, many peptidic antagonists are currently in late stage development for many of the aforementioned indications. Whilst peptidic agonists and antagonists of the GnRH receptor have been discovered and exploited clinically, they are limited to predominantly parenteral administration due to their poor oral bioavailability. Recently, several small molecule GnRH antagonist series have been discovered offering the prospect of orally active therapeutics based on GnRH receptor antagonism. This article will review the current medicinal chemistry literature and structure activity relationships known for non-peptidic GnRH receptor antagonists.