pulmonary fibrosis

Pirfenidone (AMR69) inhibits the production of CCL2 and CCL12 in fibroblasts and also decreases TGF-β2 protein levels. Pirfenidone is an antifibrotic agent that is commonly used in studies related to pulmonary fibrosis and also has anti-inflammatory activity.

TD139 is a small molecule inhibitor of inhaled galectin-3 (Gal-3) with potential anti-fibrotic activity, commonly used in the study of idiopathic pulmonary fibrosis.

Autotaxin-IN-4 is an Autotaxin inhibitor. It has the potential to treat idiopathic pulmonary fibrosis.

GLPG1205 is a potent, orally active GPR84 (G protein-coupled receptor) antagonist with anti-inflammatory activity. GLPG1205 shows good PK PD characteristics and can be used to study pulmonary fibrosis.

LPA1 receptor antagonist 1(LPA1 R antagonist 1) is a selective and potent lysophosphatidic acid (LPA1) receptor antagonist (IC50 : 25 nM) for the study of idiopathic pulmonary fibrosis.

Bersiporocin is a novel prolyl-tRNA synthetase (PRS) inhibitor that exerts antifibrotic effects through downregulation of collagen synthesis and is well tolerated in the clinic. In cellular and animal models of idiopathic pulmonary fibrosis (IPF), DWN12088 significantly reduced collagen synthesis and improved lung function.

JNJ-49095397 (RV568) is a selective p38 MAPK-α and p38 MAPK--γ kinase inhibitor with anti-inflammatory activity and potential antiviral activity for chronic obstructive pulmonary disease (COPD), cystic fibrosis, and respiratory syncytial virus infection.

Aucuparin (2,6-dimethoxy-4-phenylphenol) is a plant antibiotic with anti-inflammatory activity. Aucuparin inhibited pulmonary fibrosis in mouse models induced by bleomycin (BLM). ABTS and FRAP showed clear scavenging activity. Aucuparin inhibited superoxide production of human neutrophils induced by fmlp, and its IC50 was 17.0μM.

Lonidamine (Diclondazolic Acid) is an indazole carboxylic acid derivative, principally inhibiting aerobic glycolytic activity, by its effect on mitochondrially-bound hexokinase (HK).

Methacycline hydrochloride (Rondomycin) is a broad-spectrum semisynthetic antibiotic related to TETRACYCLINE but excreted more slowly and maintaining effective blood levels for a more extended period.

Macitentan (ACT-064992) is an endothelin receptor antagonist utilized in the treatment of pulmonary arterial hypertension (PAH).

BAY-6672 is a selective human prostaglandin F (FP) receptor antagonist that is highly potent (IC50=11 nM), orally available and well permeable. It exerts antifibrotic effects by inhibiting prostaglandin F2α (PGF₂α) activity through antagonizing the FP receptor, and has in vivo efficacy in animal models of idiopathic pulmonary fibrosis (IPF).

SSR69071 is a potent, orally active, and selective inhibitor of neutrophil elastase, displaying higher affinity for human elastase (Ki = 0.0168 nM) compared to rat (Ki = 3 nM), mouse (Ki = 1.8 nM), and rabbit (Ki = 58 nM) elastases [2]. It reduces myocardial infarct size following ischemia-reperfusion injury [1] and has potential for treating chronic obstructive pulmonary diseases, asthma, emphysema, cystic fibrosis, and various inflammatory diseases.

UNC0379 is a selective, substrate-competitive inhibitor of the lysine methyltransferase (SETD8).

Rupatadine (UR-12592, rupatadine) is a potent and orally available dual antagonist of PAF and histamine H1 receptors with Ki values of 0.55 μM and 0.1 μM, respectively, which provides relief of allergic symptoms and anti-inflammatory properties, and is used in allergic rhinitis and chronic urticaria.

Talabostat (PT100, Val-boroPro) is a potent, nonselective and orally available dipeptidyl peptidase IV (DPP-IV) inhibitor with a Ki of 0.18 nM. Talabostat is a nonselective DPP-IV inhibitor, inhibiting DPP8 9, FAP, DPP2 and some other DASH family enzymes essentially as potently as it inhibits DPP-IV[1]. Talabostat stimulates the immune system by triggering a proinflammatory form of cell death in monocytes and macrophages known as pyroptosis. The inhibition of two serine proteases, DPP8 and DPP9, activates the proprotein form of caspase-1 independent of the inflammasome adaptor ASC[2]. Talabostat competitively inhibits the dipeptidyl peptidase (DPP) activity of FAP and CD26 DPP-IV, and there is a high-affinity interaction with the catalytic site due to the formation of a complex between Ser630 624 and the boron of talabostat[3]. Talabostat can stimulate immune responses against tumors involving both the innate and adaptive branches of the immune system. In WEHI 164 fibrosarcoma and EL4 and A20 2J lymphoma models, PT-100 causes regression and rejection of tumors. The antitumor effect appears to involve tumor-specific CTL and protective immunological memory. Talabostat treatment of WEHI 164-inoculated mice increases mRNA expression of cytokines and chemokines known to promote T-cell priming and chemoattraction of T cells and innate effector cells[3]. Talabostat treated mice show significant less fibrosis and FAP expression is reduced. Upon PT100 treatment, significant differences in the MMP-12, MIP-1α, and MCP-3 mRNA expression levels in the lungs are also observed. Treatment with PT100 in this murine model of pulmonary fibrosis has an anti-fibro-proliferative effect and increases macrophage activation[4]. [1]. Connolly BA, et al. Dipeptide boronic acid inhibitors of dipeptidyl peptidase IV: determinants of potencyand in vivo efficacy and safety. J Med Chem. 2008 Oct 9;51(19):6005-13. [2]. Okondo MC, et al. DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis. Nat Chem Biol. 2017 Jan;13(1):46-53. [3]. Adams S, et al. PT-100, a small molecule dipeptidyl peptidase inhibitor, has potent antitumor effects and augments antibody-mediated cytotoxicity via a novel immune mechanism. Cancer Res. 2004 Aug 1;64(15):5471-80. [4]. Egger C, et al. Effects of the fibroblast activation protein inhibitor, PT100, in a murine model of pulmonary fibrosis. Eur J Pharmacol. 2017 Aug 15;809:64-72.

Ziritaxestat (GLPG1690), an autotaxin inhibitor, currently being evaluated in an exploratory phase 2 study in idiopathic pulmonary fibrosis patients.

1. Peiminine (Raddeanine) is an effective inhibitor for lung inflammation and pulmonary fibrosis in a rat model of bleomycin-induced lung injury.

BMS-986278 is an orally active and potent hemophosphatidic acid receptor 1 (LPA1) antagonist with Kb values of 6.9 nM and 4.0 nM for human and mouse LPA1, respectively.BMS-986278 may be investigated for use in idiopathic pulmonary fibrosis.

Talniflumate (Somalgen) is a calcium-activated chloride channel (hCLCA1 mCLCA3) blocker that reduces mucin synthesis and releases in animal models and cell culture. It possesses anti-inflammatory actions via inhibition of Cox (cyclooxygenase) and inhibits Cl- HCO3- exchange activity. It also increases survival in a cystic fibrosis mouse model of the distal intestinal obstructive syndrome.

CT52923 is a selective, orally active antagonist of platelet-derived growth factor receptor (PDGFR), functioning as an ATP-competitive inhibitor. It has versatile applications for researching pathological diseases such as atherosclerosis, glomerulonephritis, liver cirrhosis, pulmonary fibrosis, and cancer.

TGFβ1-IN-2, a derivative of diarylacylhydrazones, effectively inhibits fibroblast activation and proliferation and holds potential for idiopathic pulmonary fibrosis (IPF) research [1].

TGFβ1-IN-3, a diarylhydrazone derivative, inhibits fibroblast activation and proliferation, positioning it as a candidate compound for the treatment of idiopathic pulmonary fibrosis (IPF).

Autotaxin-IN-5 is an Autotaxin inhibitor. It has the potential to treat idiopathic pulmonary fibrosis.