Translational engagement of LPA1_{1} receptor in skin fibrosis: from dermal fibroblasts of patients with scleroderma to Tsk1 mouse

BACKGROUND AND PURPOSE: Genetic deletion and pharmacological studies suggest a role for lysophosphatidic acid receptor-1 (LPA$_{1}$ receptor) in fibrosis. We investigated the therapeutic potential in systemic sclerosis (SSc) of a new orally active selective LPA$_{1}$ receptor antagonist using dermal fibroblasts from patients and animal model of skin fibrosis. EXPERIMENTAL APPROACH: Dermal fibroblast and skin biopsies from SSs patients were used. Myofibroblast differentiation, gene expression and cytokine secretion were measured following LPA and/or SAR100842 treatment. Therapeutic effect of SAR100842 was assessed in the tight skin mouse model-1 (Tsk1). KEY RESULTS: SAR100842 is equipotent against various LPA isoforms. SSc dermal fibroblasts and skin biopsies expressed high levels of LPA$_{1}$ receptor. The LPA functional response (Ca$^{2+}$ ) in SSc dermal fibroblasts was fully antagonized with SAR100842. LPA induced myofibroblast differentiation in SSc dermal and IPF lung fibroblasts and the secretion of inflammatory markers and activated Wnt markers. Results from SSc dermal fibroblasts mirror those obtained in a mouse Tsk1 model of skin fibrosis. Using a therapeutic protocol, SAR100842 consistently reversed dermal thickening, inhibited myofibroblast differentiation and reduced skin collagen content. Inflammatory and Wnt pathway markers were also inhibited by SAR100842 in the skin of Tsk1 mice. CONCLUSION: The effects of SAR100842 on LPA -induced inflammation and on mechanisms linked to fibrosis like myofibroblast differentiation and Wnt pathway activation indicate that LPA$_{1}$ receptor activation plays a key role in skin fibrosis. Our results support the therapeutic potential of LPA$_{1}$ receptor antagonists in systemic sclerosis

Novel β‑Amino Acid Derivatives as Inhibitors of Cathepsin A

Cathepsin A (CatA) is a serine carboxypeptidase distributed between lysosomes, cell membrane, and extracellular space. Several peptide hormones including bradykinin and angiotensin I have been described as substrates. Therefore, the inhibition of CatA has the potential for beneficial effects in cardiovascular diseases. Pharmacological inhibition of CatA by the natural product ebelactone B increased renal bradykinin levels and prevented the development of salt-induced hypertension. However, so far no small molecule inhibitors of CatA with oral bioavailability have been described to allow further pharmacological profiling. In our work we identified novel β-amino acid derivatives as inhibitors of CatA after a HTS analysis based on a project adapted fragment approach. The new inhibitors showed beneficial ADME and pharmacokinetic profiles, and their binding modes were established by X-ray crystallography. Further investigations led to the identification of a hitherto unknown pathophysiological role of CatA in cardiac hypertrophy. One of our inhibitors is currently undergoing phase I clinical trials