Among these progressive-fibrosing ILDs, the most common is idiopathic pulmonary fibrosis (IPF), characterized by a very poor prognosis. 1 The most relevant ILDs may be associated with a progressive fibrosing phenotype and these ILDs are classified with a term known as progressive-fibrosing rare diseases. This disorganized damaged tissue impairs the vital role of the lungs in respiration with devastating consequences in terms of functional capacity, quality of life, and increased mortality. The pathological deposition of collagen and other connective tissue proteins causes progressive scarring and fibrosis. Interstitial lung diseases (ILDs) are a numerous and heterogeneous group of diseases that affect lung interstitium, a thin layer of cells and tissue matrix between the alveoli, which contain blood vessels and cells that help support the alveoli, allowing efficient gas exchange.

Millions of people worldwide suffer from lung diseases that affect the whole respiratory system including the airways, the air sacs (alveoli), lung interstitium, blood vessels, and pleura.

The results highlighted in this manuscript may pave the way for the identification of first-in-class molecules for the treatment of IPF. The efficacy of analog 6h was also determined in a validated human lung model of TGF-β1-dependent fibrogenesis. The best performing analogs were tested for their efficacy in inhibiting fibrotic sphere formation and cell viability, proving their capability in reverting the IPF phenotype. Structural analysis on 6h and structure-activity relationship studies contributed to the optimization of the binding mode of the new molecules. Their inhibitory potency was combined with low in vitro and in vivo toxicity. We herein developed a series of novel hHDAC6 inhibitors, coupled to low inhibitory potency over hHDAC1 and hHDAC8, as potential pharmacological tools for IPF treatment. IPF has been associated with aberrant HDAC activities confirmed by our immunohistochemistry studies on HDAC6 overexpression in IPF lung tissues.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by a progressive fibrosing phenotype.

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