Urea-based lysophosphatidic acid receptor 1 antagonists as potential migrastatics for triple-negative breast cancer

We previously described the discovery of carbamate-derived small molecules as potent and selective lysophosphatidic acid receptor 1 (LPA₁) antagonists. To further expand the library of LPA₁ antagonists and potentially enhance their stability and potency, a urea moiety was introduced in replacement of the carbamate group and a series of LPA₁ antagonists based on a urea scaffold were synthesized and evaluated. Within this series, several compounds exhibited potent LPA₁ antagonism. Notably, compound 5f emerged as one of the most potent, with an IC₅₀ of 215.2 nM in the cAMP assay and 7.9 nM in the calcium mobilization assay. Compound 5f demonstrated the ability to block LPA-induced cell migration and invasion in the triple-negative breast cancer cell line MDA-MB-231. These findings support further in vivo evaluation of compound 5f as a potential therapeutic agent targeting LPA₁. The development of these urea-derived LPA₁ antagonists in this study has expanded the repertoire of LPA₁ antagonists and holds potential for the development of a novel therapy for metastatic triple-negative breast cancer.