Background:

BIO5192 is a small molecule inhibitor of integrin α4β1 with an IC50 value of 1.8 ± 0.7 nM [1].

Integrin α4β1 is important in inflammatory processes. In the inflammatory processes, α4β1 regulates the migration of lymphocytes into inflamed tissues [1].

In assays using cells expressing α4β7, α9β1, α2β1, and αIIbβ3, BIO5192 showed high selectivity for α4β1. The affinity of BIO5192 for α4β1 was 250- to 1000-fold higher than for α4β7 that shared many ligands the same as α4β1. BIO5192 bound even less tightly to α2β1 and αIIbβ3. A significant but low level (KD=140 nM) of binding was seen on α9β1 in buffer containing 1 mM Mn2+ [1].

After 24 h of BIO5192 treatment, the lymphocyte count rose about 1.5-fold. Half as many cells as when TA-2 was given were released into the circulation following the treatment with BIO5192. Data showed that BIO5192 remained bound to 100% of the α4β1 receptors for 24 h and 50% for 48 h. Rats treated with BIO5192 at 30 mg/kg, s.c. showed a 1- to 2-day shift when dosed q.d. and a 3-day delay in the onset of disease EAE when dosed b.i.d. compared with the control groups. The delay in the onset of EAE in the BIO5192-treated group was consistent with the finding that bound BIO5192 would occupy α4β1 long beyond the point at which the BIO5192 was no longer detected in blood [1].

Reference:
[1].  Leone DR, Giza K, Gill A, et al. An assessment of the mechanistic differences between two integrin α4β1 inhibitors, the monoclonal antibody TA-2 and the small molecule BIO5192, in rat experimental autoimmune encephalomyelitis[J]. Journal of Pharmacology and Experimental Therapeutics, 2003, 305(3): 1150-1162.