Development of a multigram synthesis of the bradykinin receptor 2 agonist FR‐190997 and analogs thereof

Abstract

Using Fujisawa's B2R agonist FR-190997, we recently demonstrated for the first time that agonism at the bradykinin receptor type 2 (B2R) produces substantial antiproliferative effects. FR-190997 elicited an EC 50 of 80 nM in the triple-negative breast cancer cell line MDA-MB-231, a much superior performance to that exhibited by most approved breast cancer drugs. Consequently, we initiated a program aiming primarily at synthesizing adequate quantities of FR-190997 to support further in vitro and in vivo studies toward its repurposing for various cancers and, in parallel, enable the generation of novel FR-190997 analogs for an SAR study. Prerequisite for this endeavor was to address the synthetic challenges associated with the FR-190997 scaffold, which the Fujisawa chemists had constructed in 20 steps, 13 of which required chromatographic purification. We succeeded in developing a 17-step synthesis amenable to late-stage diversification that eliminated all chromatography and enabled access to multigram quantities of FR-190997 and novel derivatives thereof, supporting further anticancer research based on B2R agonists.

Scalable Synthesis of Cinnamylamines Via the Heck Reaction: Application in the Synthesis of Abamine, Naftifine and Reboxetine

“…Initially, we tested the conditions we had previously employed in the classical Heck reaction of ethyl acrylate with aryl bromides using Pd(OAc) 2 / t Bu 3 P (3 and 6 mol % respectively) and Et 3 N in DMF [26a] . This however, including variations in the solvent and base, led to a complex mixture of products.…”