BMS-566419 is a potent inosine monophosphate dehydrogenase (IMPDH) inhibitor (IC50 = 17 nM). BMS-566419 inhibits proliferation of human T-lymphoblasts and PBMCs in vitro. BMS-566419 reduces paw swelling in a rat adjuvant arthritis model. BMS-566419 is orally available. In experimental rat model BMS-566419 by oral administration showed a significant and dose-dependent suppressive effect on UUO-induced renal fibrosis in histopathological experiments. BMS-566419 treatment also decreased collagen content, as indicated by hydroxyproline concentration, and the expression of collagen type 1 mRNA. BMS-566419 also decreased the expression of mRNA for both MCP-1 and TGF-β1. The antifibrotic effects of treatment with BMS-566419 at 60 mg/kg seemed comparable to those with MMF at 40 mg/kg. These results suggest that BMS-566419 and other chemically synthesized IMPDH inhibitors have beneficial pharmacological effects similar to those of MMF, and are potential pharmaceutical candidates in the treatment of fibrotic renal disease, including CAN.

BMS-509744 is a potent interleukin-2 inducible T cell kinase (ITK) inhibitor (IC50 = 19 nM). It displays 200-fold selectivity over Tec family kinases and 55-fold selectivity over other kinases tested. BMS-509744 reduces HIV infection of primary CD4+ T cells and attenuates the establishment of HIV infection in vitro. BMS-509744 also reduces T cell proliferation and IL-2 production in vitro. BMS-509744 reduces TCR-induced functions including PLCgamma1 tyrosine phosphorylation, calcium mobilization, IL-2 secretion, and T-cell proliferation in vitro in both human and mouse cells. BMS-509744 suppresses the production of IL-2 induced by anti-TCR antibody administered to mice. BMS-509744 also significantly diminishes lung inflammation in a mouse model of ovalbumin-induced allergy/asthma.

BMS-453 (BMS-189453) is a potent and selective RAR agonist and a potent testicular toxin. In Sprague Dawley rats at daily oral doses of 15, 60, or 240 mg/kg for 1 month, BMS-189453 produced increases in leukocyte counts, alkaline phosphatase and alanine aminotransferase levels, and marked testicular degeneration and atrophy at all doses. BMS-189453 reduced MMP-1 expression in HIG-82 synovial fibroblasts in culture. BMS-189453 treatment blocked the clinical progression of arthritis beyond soft tissue inflammation in the CIA model. In the SCWA model, BMS-189453 treatment resulted in significantly reduced swelling with no notable progression to joint distortion/destruction. Improvement in clinical and histologic variables in 2 separate animal models, along with simultaneous reduction in MMP expression in the affected joint, suggests that RAR antagonists such as BMS-189453 may be useful as agents to treat rheumatoid arthritis and for determining the role of MMP in disease progression.