• 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • Epoxomicin As previously stated the most unexpected finding


    As previously stated, the most unexpected finding from this series of compounds was the identification of a dimethyl isoxazole side chain that gave dramatically improved binding over the parent compounds. Holding this piece of the molecule constant, a series of analogs were made to further understand the SAR of the core sultam ring. shows the synthesis of a ring-deleted analog of . 2-Methyl-indole-3-carbaldehyde () was alkylated and treated with ()-2-phenylethenesulfonamide to give imine . AlCl mediated addition of vinyl Grignard gave compound . The key step of this sequence is the ring-closing metathesis of to form , which occurs in good yield in refluxing DCM. Hydrogenation of resulted in C–N bond cleavage giving the undesired ring-opened analog . However, conjugate reduction via sodium borohydride gave the desired key intermediate , which was alkylated and deprotected to give the desired product, . Interestingly, Epoxomicin promoted deprotection to give gave a complex mixture of products and therefore a one-pot transesterification/saponification was used to remove the -butyl ester. Exploration of the stereogenic carbon was explored via AlCl mediated addition of a methyl Grignard to compound as outlined in . Addition of the dimethylisoxazole tail followed by standard deprotection of the -butyl ester gave the desired compound . As illustrated in , addition of a methyl group to the stereogenic carbon () results in only a threefold loss of potency. Complete removal of the ‘northern’ aromatic ring () results in only a modest loss of affinity. This taken together with the results in , suggests that the primary driver of potency for these molecules is the combination of the ‘southern’ 2-methyl indole core and the strategically placed isoxazole ring. The southern carboxylate/indole moiety presumably anchors the molecule in such a way that allows the isoxazole to make one or more key hydrogen bonds with the receptor. A few of the most active compounds were screened for selectivity against the other prostaglandin D2 receptor, DP1. Since the compounds described herein are ultimately relatives of Ramatroban, a Thromboxane-A2 (TXA2) receptor antagonist, we also screened for selectivity against the TXA2 receptor (TP). The results are shown in . As can be seen, these compounds are clearly very selective for CRTh2 over the DP1 and TP receptors. The assays described above are receptor-binding assays which do not directly measure the function (antagonism/agonism) of the compounds. To this end, compound was evaluated in a FLIPR-based functional assay in order to verify that one of the most potent compounds of this series was, in fact, an antagonist of the CRTh2 receptor in a cellular context. Gratifyingly, compound was shown Epoxomicin to block the activation of the receptor by PGD, with a of 28nM.
    Introduction Prostaglandin D2 (PGD2) is a downstream metabolite and a major prostanoid released by IgE-activated mast cells in response to allergen provocation and acts as central mediator in asthma and inflammation [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]. Two G-protein coupled receptors namely DP1 and CRTh2 (also called DP2) mediate the effect of PGD2 [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]. Allergic disorders are caused by interaction between immunologically activated mast cells and Th2 lymphocytes where CRTh2 plays the dominant role in mediating this interaction [7]. CRTh2 is predominantly expressed on Th2 cells, eosinophils and basophils which play a role in pathogenesis of inflammatory diseases by promoting chemotaxis of Th2 cells and degranulation of eosinophils both in vivo and in vitro which suggest that CRTh2 may directly mediate the recruitment of inflammatory cells in allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]. Studies have reported that mice deficient in CRTh2 have been described to be resistant to experimentally induced allergic asthma, suggesting that CRTh2 might play a central role in the pathogenesis of allergic diseases [13], [16]. Further data in animal models have highlighted the role of CRTh2 in mast cell dependent activation of Th2 cells in chronic allergic skin inflammation and eosinophilic airway inflammation [3], [7]. Subsequently, a considerable number of studies have contributed to the validation of CRTh2 as an anti-inflammatory target.