A new class of PDE4 inhibitors were designed and synthesized via the InCl3 mediated heteroarylation of indoles and their further derivatization through the Pd(II)-catalyzed CH activation strategy. This effort allowed us to discover a series of 2-(1H-indol-3-yl)-quinoxaline based inhibitors possessing PDE4B selectivity over PDE4D and PDE4C. One of these compounds i.e. 3b (PDE4B IC50 = 0.39 ± 0.13 μM with ∼27 and > 250 fold selectivity for PDE4B over PDE4D and C, respectively) showed effects in Zebrafish experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis when dosed at 3, 10 and 30 mg/kg intraperitoneally. Indeed, it halted the progression of the disease across all these doses tested. At an intraperitoneal dose of 30 mg/kg the compound 3b showed promising effects in adjuvant induced arthritic rats. The compound reduced paw volume, inflammation and pannus formation (in the knee joints) as well as pro-inflammatory gene expression/mRNA levels significantly in arthritic rats. Moreover, this compound was found to be selective towards PDE4 over other families of PDEs in vitro and safe when tested for its probable toxicity (e.g. teratogenicity, hepatotoxicity and cardiotoxicity) in Zebrafish.
Keywords: Arthritis; Indole; Multiple sclerosis; PDE4; Quinoxaline.
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