Immunomodulation 2Saturday, October 13, 2007, 15:30 - 17:00
BNC-245 – a novel compound for multiple sclerosis treatmentE. Andriambeloson, S. Wagner, L. Gorj, J. Bindler, J. Mould, B. Flynn (Illkirch, F; Adelaide, AUS)
The Kv1.3 ion channel modulates the function of autoreactive effector memory T-cells (TEM) which have been implicated in the pathogenesis of autoimmune diseases such multiple sclerosis (MS) and rheumatoid arthritis.
Under whole cell patch clamp conditions, BNC-245 exhibits 5 fold selectivity for Kv1.3 over Kv1.1 or Kv1.5 channels with an IC50 of 75 nM. Consistent with the role of Kv1.3 in T cell activation, BNC-245 reduces the proliferation of MBP- activated memory T cells in a dose dependent manner. Pharmacokinetic studies indicate that BNC-245 has good drug like properties with an oral bioavailability of 90% and a half life of 5 hr.
In the present study, we demonstrate in-vivo efficacy of BNC-245, a novel Kv1.3 channel blocker, in ovalbumin -induced delayed type hypersensitivity (DTH) and myelin basic protein (MBP) –induced experimental autoimmune encephalomyelitis (EAE) in Lewis rats.
BNC-245 administered PO as a single dose on the day of albumin challenge, significantly reduced the DTH response in rats in a dose-dependent manner with a minimum effective dose <= 0.1 mg/kg. In EAE-rats, BNC-245 (30 mg/kg/d) administered from days 8 to 12 post-MBP significantly reduced the severity of the disease (area under curve reduced to 56% of control).
Together, these results indicate that BNC-245 modulates TEM function and attenuates neurological deficits in a rat model of MS, most probably via inhibition of Kv1.3 K+ channels. BNC-245 could therefore provide a novel for treatment for MS and other autoimmune diseases.