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Discovery of a Potent, Selective, and Orally Bioavailable Tool Compound for Probing the Role of Lysophosphatidic Acid Type 2 Receptor Antagonists in Fibrotic Disorders

In this collaborative paper, recently published in J. Med. Chem., 10.1021/acs.jmedchem.2c02087, Chiesi Farmaceutici and Evotec  describe the efforts to identify a potent and selective, orally bioavailable,  Lysophosphatidic Acid Type 2 (LPA2) Receptor Antagonists to treat Idiopathic pulmonary fibrosis (IPF) or other fibrotic disorders. 

The article is an example of how early Dose to Man (eD2M) prediction can be efficiently used to guide Hit to Lead and Lead Optimization when potency and metabolic stability are the main parameters to be optimized. eD2M exploits only in vitro parameters (activity in the primary assay and metabolic stability in human microsomes) and it was extremely useful to monitor project progression and to prioritize compounds for in vivo PK studies. Starting from an LPA2 antagonist compound reported in the literature and following our multiparametric optimization strategy, we were able to identify compound 58, showing a 45000-fold eD2M improvement compared to the starting hit. Additionally, compound 58 exhibits excellent potency, selectivity, and oral in vivo PK profile, making it a suitable tool for probing the involvement of LPA2 receptors in IPF and other fibrotic processes.

IPF is a progressive and fatal disease characterized by lung fibrosis leading to an irreversible decline of the functionality of the lungs. The drugs currently available to patients can slow down the progression of the disease, but there are no treatments that can prevent or block it.

To request a copy of the article, contact the authors. For Evotec: