Edward Yin-Shiang Lin

Design and synthesis of a series of meta aniline-based LFA-1 ICAM inhibitors

A series of meta-substituted anilines were designed and synthesized to inhibit the interaction of LFA-1 with ICAM for the treatment of autoimmune disease. Design of these molecules was performed by utilizing a co-crystal structure for structure-based drug design. The resulting molecules were found to be potent and to possess favorable pharmaceutical properties.

Pyrazolone based TGFβR1 kinase inhibitors

Interruption of TGFbeta signaling through inhibition of the TGFbetaR1 kinase domain may prove to have beneficial effect in both fibrotic and oncological diseases. Herein we describe the SAR of a novel series of TGFbetaR1 kinase inhibitors containing a pyrazolone core. Most TGFbetaR1 kinase inhibitors described to date contain a core five-membered ring bearing N as H-bond acceptor. Described herein is a novel strategy to replace the core structure with pyrazolone ring, in which the carbonyl group is designed as an H-bond acceptor to interact with catalytic Lys 232.

Discovery of novel pyrazole-containing benzamides as potent RORγ inverse agonists

The nuclear receptor RORγ plays a central role in controlling a pro-inflammatory gene expression program in several lymphocyte lineages including TH17 cells. RORγ-dependent inflammation has been implicated in the pathogenesis of several major autoimmune diseases and thus RORγ is an attractive target for therapeutic intervention in these diseases. Starting from a lead biaryl compound 4a, replacement of the head phenyl moiety with a substituted aminopyrazole group resulted in a series with improved physical properties. Further SAR exploration led to analogues (e.g., 4j and 5m) as potent RORγ inverse agonists.

Structure–activity relationship of ortho- and meta-phenol based LFA-1 ICAM inhibitors

LFA-1 ICAM inhibitors based on ortho- and meta-phenol templates were designed and synthesized by Mitsunobu chemistry. The selection of targets was guided by X-ray co-crystal data, and led to compounds which showed an up to 30-fold increase in potency over reference compound 1 in the LFA-1/ICAM1-Ig assay. The most active compound exploited a new hydrogen bond to the I-domain and exhibited subnanomolar potency.