br Conclusion br Conflict of interest br Prostaglandin D PGD

Conclusion
Conflict of interest
Prostaglandin D2 (PGD) is the major prostanoid released by mast cells during allergic attacks., In human patients, allergen challenge leads to a rapid increase in the production of PGD in the airway of asthmatics, in the nasal mucosa of allergic rhinitics and in the skin of patients suffering from atopic dermatitis. Two high affinity binding G-protein-coupled receptors, the DP1 receptor and the chemoattractant receptor-homologous expressed on Th2 cells (CRTH2 or DP2), have been shown to mediate the effects of PGD. The later receptor is expressed on cell types associated with allergic inflammation, such as Th2 cells, basophils and eosinophils and its activation by PGD triggers the migration, and prevents the apoptosis of these cell types. In vivo reports in rodents have highlighted the role of CRTH2 in promoting chronic allergic skin inflammation and eosinophilic airway inflammation. CRTH2 antagonists have shown efficacy in a murine model of allergic rhinitis. More recently, an orally bioavailable CRTH2 antagonist (OC000459) successfully completed Phase IIa trials demonstrating efficacy in asthma and allergic rhinoconjunctivitis thus unambiguously establishing CRTH2 as a central player of airway inflammation. A number of medicinal chemistry programs started after the identification of non-steroidal anti-inflammatory drug indomethacin (, ) as an agonist of the CRTH2 receptor,, and that of thromboxane receptor antagonist ramatroban (, ) as an antagonist of the CRTH2 receptor. As a result a large number of CRTH2 antagonists known to date are indole acetic acids, bearing the acetic Mouse iPSC Chemical Reprogramming Cocktails Kit plus mg moiety either at position 3, exemplified with compound () or at position 1, exemplified with compound (). A variety of fused 6–5-membered ring chemotypes have arisen such as 7-azaindole acetic acids, benzimidazolyl acetic acids, spiro-indolinone acetic acids, and indolizine acetic acids, however, to the best of our knowledge, fused 5,5-membered ring systems have not been reported.
Prostaglandin D (PGD) produced by mast cells is a key mediator of asthmatic and allergic inflammatory responses. There are two known receptors of PGD: DP1 and DP2 (also known as CRTh2)., , The latter receptor is expressed on the surface of eosinophils, basophils, and Th2 cells and is responsible for PGD-induced chemotaxis in all three cell types. Moreover, CRTh2 is involved in cytokine release from Th2 cells and degranulation of eosinophils., This has led to widespread interest in antagonists of CRTh2 as potential agents for the treatment of asthma and related allergic diseases., , , , , Recent publication of the effect of CRTh2 antagonists in various animal models of asthma and allergic rhinitis have spurred further interest in the exploration of this target., , Ramatroban and its acetic acid analog (, ) have been reported to be potent antagonists of CRTh2., We previously disclosed the SAR of a series of ‘reverse Ramatroban’ analogs with similar potency to compound . In our attempts to design additional novel CRTh2 antagonists, we hypothesized that the saturated ring of compound could be excised from the tetrahydrocarbazole and instead form a bicyclic sulfonamide, as shown in . One such embodiment of this hypothesis is benzosultam . This analog seemed especially fitting given that it would retain and rigidify the cisoid geometry that sulfonamides such as Ramatroban naturally adopt. The synthesis of compound and related compounds is illustrated in . The synthesis begins with AlCl promoted electrophilic addition of compound (derived in one step from saccharin) to an indole, giving intermediate . The indole nitrogen of is alkylated with -butyl bromoacetate and the sulfonyl imine is subsequently reduced to give the benzosultam . Deprotection of the -butyl group is accomplished with TFA giving compounds .