We describe the synthesis through visible-light photocatalysis of novel functionalized tetracyclic scaffolds that incorporate a fused azabicyclo[3.2.0]heptan-2-one motif, which are structurally interesting cores with potential in natural product synthesis and drug discovery. The synthetic approach involves an intramolecular [2 + 2] cycloaddition with concomitant dearomatization of the heterocycle via an energy transfer process promoted by an iridium-based photosensitizer, to build a complex molecular architecture with at least three stereogenic centers from relatively simple, achiral precursors. These fused azabicyclo[3.2.0]heptan-2-one-based tetracycles were obtained in high yield (generally >99%) and with excellent diastereoselectivity (>99:1). The late-stage derivatization of a bromine-substituted, tetracyclic indoline derivative with alkyl groups, employing a mild Negishi C−C bond forming protocol as a means of increasing structural diversity, provides additional modularity that will enable the delivery of valuable building blocks for medicinal chemistry. Density functional theory calculations were used to compute the T 1 −S 0 free energy gap of the olefin-tethered precursors and also to predict their reactivities based on triplet state energy transfer and transition state energy feasibility.
RORγt
is an important nuclear receptor that regulates the
production of several pro-inflammatory cytokines such as IL-17 and
IL-22. As a result, RORγt has been identified as a potential
target for the treatment of various immunological disorders such as
psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure
and computer-assisted drug design led to the identification of a novel
series of tricyclic RORγt inverse agonists with significantly
improved in vitro activity in the reporter (Gal4) and human whole
blood assays compared to our previous chemotype. Through careful structure
activity relationship, several potent and selective RORγt inverse
agonists have been identified. Pharmacokinetic studies allowed the
identification of the lead molecule 32 with a low peak-to-trough
ratio. This molecule showed excellent activity in an IL-2/IL-23-induced
mouse pharmacodynamic study and demonstrated biologic-like efficacy
in an IL-23-induced preclinical model of psoriasis.
Fingolimod is an oral immunomodulating drug used in the management of relapsing-remitting multiple sclerosis (RRMS). We aim to review the published literature on ocular manifestations of fingolimod therapy and their possible underlying mechanisms. The therapeutic effects of fingolimod are mediated via sphingosine receptors, which are found ubiquitously in various organs, including lymphoid cells, central nervous system, cardiac myocytes, and smooth muscle cells. Fingolimod-associated macular oedema (FAME) is the most common ocular side effect but retinal haemorrhages and retinal vein occlusion can occur. The visual consequences appear to be mild and, in cases of FAME, resolution is often attained with discontinuation of therapy. However, in cases of retinal vein occlusion, discontinuation of fingolimod alone may not be sufficient and intra-vitreal therapy may be required. We also propose a pragmatic service pathway for monitoring patients on fingolimod therapy, which includes stratifying them by risk and visual acuity.
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