Rheumatoid arthritis (RA) is a systematic autoimmune disease that characterized by chronic synovial inflammation and progressive bone erosion [1]. RA-related joint swelling, stiffness, and chronic pain afflict roughly 1 % of the worldwide population, significantly affecting life quality and imposing a heavy socioeconomic burden [2,3]. Although nonsteroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, and disease-modifying anti-rheumatic drugs were commonly used for RA therapy at present, their clinical application is restricted due to uncertain efficacy, undesirable adverse events and difficulty of complete cure [4,5]. Thus, it is still urgent to discover novel agent with improved efficiency and minimal side effects for treating RA.

In the recent years, accumulating studies have revealed that the synovial hypoxic microenvironment serves important roles in the pathological progression of RA through inducing synovial inflammation, promoting angiogenesis and causing cartilage/bone destruction [6,7]. Hypoxia-inducible factor 1 (HIF-1), a heterodimer composed of HIF-1α and HIF-1β subunits, is a transcription factor that responds to a hypoxic environment. Under the normoxia condition, HIF-1α is hydroxylated by prolyl hydroxylases (PHD), and is subsequently degraded by von Hippel−Lindau (VHL) E3-ubiquitin-proteasomal system [8]. However, under hypoxia condition, HIF-1α is stabilized and nuclear-translocated to dimerize with HIF-1β. The HIF-1 heterodimer binds to the hypoxia responsive element (HRE) and activates transcription of a number of hypoxia-response genes which mainly mediate inflammation, angiogenesis, pannus formation, and synovial hyperplasia [9,10]. Previous studies and clinical data have highlighted that HIF-1α is overexpressed and hyperactivated in response to synovial hypoxia in RA patients and animal models [[11], [12], [13]]. Studies by our group and others have shown that blocking HIF-1α by RNA interference or pharmacological inhibition effectively attenuated inflammatory response, alleviated cartilage/bone destruction and exerted therapeutic effects on animal RA models [[14], [15], [16]]. Therefore, HIF-1 has been considered as a promising target for developing novel therapeutic agents for RA treatment.

Isoquinoline represents an important drug-like scaffold structure existing in both natural products and synthetic compounds (Fig. 1), such as berberine (1), fangchinoline (2), litcubanine A (3) and so on, which have been demonstrated with varies pharmacological properties including anti-inflammation, anti-cancer and anti-infectious effects, attracting significant interests in medicinal chemistry and drug design [[17], [18], [19], [20], [21]]. In particular, several representative compounds containing isoquinolin-1(2H)-one showed therapeutic effects against inflammatory disease, including rheumatoid arthritis, such as PARP-1 inhibitor 5-AIQ (4) [22,23], BTK inhibitor RN486 (5) [24] and PDE4 inhibitor Cpd-3k (6) [25] (Fig. 1).

In our previous work, a thiazole carboxamide fragment was identified as preliminary hits of HIF-1 inhibitor for further optimization using a cell-based HRE luciferase reporter assay [26]. Subsequently, systematic modification of hit compound was conducted in an attempt to improve potency using fragment-based approach. After five rounds of in-depth optimization, an aryl carboxamide derivative, AMSP-30m (7), was discovered as a novel HIF-1 inhibitor with potent suppressive activity on angiogenesis and metastasis in breast cancer. Briefly, for fragment growing, phenyl was introduced to replace the methyl group, resulting in an increase of activities. Then, through substituents screening, ortho-fluorine substitution on the N-phenethyl was found to dramatically increase activity. Finally, the substituents of 6-phenyl were also screened to obtain the 2-methoxyphenyl derivative (7) as the most active inhibitor (Fig. 2) [26]. Subsequent biological evaluation showed that AMSP-30m (7) also exhibited therapeutic effects on arthritis in rat through inducting synoviocytes apoptosis, inhibiting inflammatory response and attenuating synovial angiogenesis [15,16]. In the present work, considering the application of isoquinolin-1(2H)-one as ideal scaffold in discovering anti-inflammation agents, we introduced isoquinolin-1(2H)-one to replace the ami moiety using scaffold-hopping strategy as part of our continuous modification of AMSP-30m in order to further improve its anti-inflammation activity, especially for RA treatment (Fig. 2).