Endocrine therapies in the treatment of early and metastatic estrogen receptor α positive (ERα+) breast cancer (BC) are greatly limited by de novo and acquired resistance. Selective estrogen receptor degraders (SERDs) like fulvestrant provide new strategies for endocrine therapy combinations due to unique mechanisms. Herein, we disclose our structure-based optimization of LSZ102 by replacing 6-hydroxybenzothiophene with 6H-thieno­[2,3-e]­indazole. Subsequent acrylic acid degron modifications led us to identify compound 40 as the preferred candidate. In general, compound 40 showed much better pharmacological profiles than the lead LSZ102, exhibiting growth inhibition of wild-type or tamoxifen-resistant MCF-7 cells, potent ERα degradation, together with superior pharmacokinetic properties, directional target tissue distribution including the brain, and robust antitumor efficacy in the mice breast cancer xenograft model. Currently, 40 is being evaluated in preclinical trials.

Recently, we reported the promising activity of a series of novel bicyclic pyridine derivatives as antiplatelet agents. Herein, we describe a modified and improved chemical synthesis of the lead compound, 1-(3-cyano-5-oxo-5,7-dihydrofuro[3,4-b] pyridin-2-yl)-4-methyl-N-((4-methylbenzyl)sulfonyl)piperidine-4carboxamide (1), with the aim to produce from milligrams to 10 g of the pure compound that is necessary for the preclinical studies. This novel process is one step shorter and starts from cheap materials, achieving a sevenfold of the total yield from 0.7 % to 5 %. Additionally, it also avoids the use of palladium on carbon as well as all of the steps involve simple purifications without chromatography.