Discovery of Highly Selective and Orally Active Lysophosphatidic Acid Receptor-1 Antagonists with Potent Activity on Human Lung Fibroblasts
| Autor: | Yonglin Ren, Ryan Craig Schoenfeld, Adrian J. Fretland, Maria E. Fuentes, Kung-Ching Chang, Yimin Qian, Rachid Hamid, Yun Chen, Achyutharao Sidduri, Matthew Michael Hamilton, Christopher S. Stevenson, Gabriel Stephen Deems, Lin Zhang, Terry Truitt, Dramane Ibrahim Laine, Arjun Narayanan, Ruoqi Peng, David C. Budd, Matthew C. Lucas, Rama K. Kondru, Ruben Alvarez Sanchez |
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| Rok vydání: | 2012 |
| Předmět: |
Gene isoform
Spectrometry Mass Electrospray Ionization Magnetic Resonance Spectroscopy Phospholipid Antagonist Administration Oral Stimulation Fibroblasts Pharmacology Mice Structure-Activity Relationship chemistry.chemical_compound chemistry Drug Discovery Lysophosphatidic acid Knockout mouse Animals Humans Pyrazoles Molecular Medicine Structure–activity relationship lipids (amino acids peptides and proteins) Receptors Lysophosphatidic Acid Receptor Lung |
| Zdroj: | Journal of Medicinal Chemistry. 55:7920-7939 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Lysophosphatidic acid is a class of bioactive phospholipid that mediates most of its biological effects through LPA receptors, of which six isoforms have been identified. The recent results from LPA1 knockout mice suggested that blocking LPA1 signaling could provide a potential novel approach for the treatment of idiopathic pulmonary fibrosis. Here, we report the design and synthesis of pyrazole- and triazole-derived carbamates as LPA1-selective and LPA1/3 dual antagonists. In particular, compound 2, the most selective LPA1 antagonist reported, inhibited proliferation and contraction of normal human lung fibroblasts (NHLF) following LPA stimulation. Oral dosing of compound 2 to mice resulted in a dose-dependent reduction of plasma histamine levels in a murine LPA challenge model. Furthermore, we applied our novel antagonists as chemistry probes and investigated the contribution of LPA1/2/3 in mediating the pro-fibrotic responses. Our results suggest LPA1 as the major receptor subtype mediating LPA-induced proliferation and contraction of NHLF. |
| Databáze: | OpenAIRE |
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