1. Discovery of a Potent, Selective, and Orally Bioavailable Tool Compound for Probing the Role of Lysophosphatidic Acid Type 2 Receptor Antagonists in Fibrotic Disorders
- Author
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Armani, Elisabetta, Rizzi, Andrea, Iotti, Nicolò, Saccani, Francesca, Di Lascia, Maria Rosaria, Tigli, Laura, Pappani, Alice, Marchini, Gessica, Murgo, Annalisa, Capelli, Anna Maria, Delcanale, Maurizio, Puccini, Paola, Villetti, Gino, Civelli, Maurizio, Beato, Claudia, Giuliani, Marta, Mundi, Claudia, Murarolli, Francesca, Pagano, Mafalda, Raveglia, Luca F., Remelli, Rosaria, and Amari, Gabriele
- Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease characterized by lung fibrosis leading to an irreversible decline of lung function. Current antifibrotic drugs on the market slow down but do not prevent the progression of the disease and are associated with tolerability issues. The involvement of lysophosphatidic acid receptor 2 (LPA2) in IPF is supported by LPA2knockdown studies. To further validate the role of LPA2receptors in modulating IPF and potentially other fibrotic processes, a potent and selective LPA2receptor antagonist with a good pharmacokinetic (PK) profile is needed. Herein, we report the medicinal chemistry exploration that led to the discovery of a new class of highly potent and selective LPA2antagonists. Among them, compound 58exhibits excellent potency, selectivity, and oral PK profile, making it a suitable tool for probing the involvement of LPA2receptors in IPF and other fibrotic processes.
- Published
- 2023
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