Discovery of Novel 4,5,6,7-Tetrahydro-7-pyrazolo[3,4-]pyridin-7-one Derivatives as Orally Efficacious ATX Allosteric Inhibitors for the Treatment of Pulmonary Fibrosis.

Pulmonary fibrosis (PF) is a progressive, fatal lung disease lacking effective treatments. Autotaxin (ATX) plays a crucial role in exacerbating inflammation and fibrosis, making it a promising target for fibrosis therapies. Herein, starting from PAT-409 (Cudetaxestat), a series of novel ATX inhibitors bearing 1-indole-3-carboxamide, 4,5,6,7-tetrahydro-7-pyrazolo[3,4-]pyridin-7-one, or 4,5,6,7-tetrahydro-1-pyrazolo[4,3-]pyridine cores were designed based on the structure of ATX hydrophobic tunnel.

Recent advances and challenges of revolutionizing drug-resistant tuberculosis treatment.

Tuberculosis (TB), an infectious disease induced by Mycobacterium tuberculosis, is one of the primary public health threats all over the world. Since the prevalence of first-line anti-TB agents, the morbidity and mortality issues of TB descended obviously. Nevertheless, the emergences of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains, the double prevalence of HIV-TB co-infection, and the insufficiency of plentiful health care have led to an increased incidence of TB.

Structure-guided design of potent JAK1-selective inhibitors based on 4-amino-7H-pyrrolo[2,3-d]pyrimidine with anti-inflammatory efficacy.

In a continuous effort to develop Janus kinase 1 (JAK1)-selective inhibitors, a novel series of 4-amino-7H-pyrrolo[2,3-d]pyrimidine derivatives bearing the piperidinyl fragment were designed and synthesized according to a combination strategy. Through enzymatic assessments, the superior compound 12a with an IC value of 12.6 nM against JAK1 was identified and a 10.

Discovery of novel phenyl triazole analogs as TRK/ALK dual inhibitors with prospective antitumor effects.

The exploration of novel anaplastic lymphoma kinase (ALK) and tropomyosin receptor kinase (TRK) dual inhibitors tended to serve as targeted treatment of cancer. Herein, a series of phenyl triazole derivatives were designed and synthesized as ALK/TRK dual regulators based on structure-based drug design (SBDD) strategy and were evaluated for antiproliferative activity by MTT assay. Accordingly, all compounds showed surprising cytotoxicity with IC values below 10 μM on KM12, H2228 and KARPAS299 cell lines.