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.