alpha4beta1-integrin blockade and cyclosporine decreases the prevalence and severity of transplant vasculopathy in a rat transplant model.

BACKGROUND: Transplant vasculopathy leads to neointimal proliferation of allograft arteries, and alpha4beta1-integrin (very late antigen-4 [VLA-4]) seems to play an important role in the pathogenesis. This study evaluates the effect of a new, synthetic, VLA-4 blocker (S3429) on transplant vasculopathy in a rat cardiac transplant model. METHODS: After transplantation (Lewis to Fisher), rats were divided randomly into 6 therapy groups: Group 1, n = 14, saline solution (vehicle); Group 2, n = 14, 3 mg/kg/day cyclosporine; Group 3, n = 21, 10 mg/kg/day S3429 + 3 mg/kg/day cyclosporine; Group 4, n = 21, 5 mg/kg/day S3429 + 3 mg/kg/day cyclosporine; Group 5: n = 21, 10 mg/kg/day S3429; Group 6, n = 21, 5 mg/kg/day S3429. Cyclosporine was given continuously until rats were killed. S3429 was either given for the entire study time or was discontinued after 20 days and animals were killed at Day 80. Twenty-eighty days after grafting, we assessed vasculopathy prevalence and mean vessel occlusion in coronary arteries. RESULTS: Cyclosporine decreased the prevalence of vasculopathy and mean vessel occlusion compared with controls. We observed a further decrease in prevalence and mean vessel occlusion with 80 days of therapy with S3429 and cyclosporine. After discontinuing S3429 therapy at Day 20, prevalence and mean vessel occlusion increased to values seen in cyclosporine-treated animals at Day 80. S3429 alone decreased mean vessel occlusion only within the first 20 days compared with controls but had no effect on the prevalence of vasculopathy. CONCLUSION: Because of the further decrease with S3429 therapy and the dramatic increase after discontinuation of S3429 therapy, we conclude that blocking VLA-4 receptors may prevent the development of transplant vasculopathy.

alpha(v)beta(3) Antagonists based on a central thiophene scaffold.

A series of novel, highly potent alpha(v)beta(3) antagonists based on a thiophene scaffold and containing an acylguanidine as an Arg-mimetic is described. A number of structural features, such as cyclic versus open guanidine and a variety of lipophilic side chains, carbamates, sulfonamides and beta-amino acids were explored with respect to inhibition of alpha(v)beta(3) mediated cell adhesion and selectivity versus alpha(IIb)beta(3) binding. In addition, compound 19 was found to be active in the TPTX model of osteoporosis.

Discovery of an orally active non-peptide fibrinogen receptor antagonist based on the hydantoin scaffold.

Antagonists of the platelet fibrinogen receptor (GP IIb/IIIa receptor) are expected to be a promising new class of antithrombotic agents. The binding of fibrinogen to the fibrinogen receptor depends on an Arg-Gly-Asp-Ser (RGDS) tetrapeptide recognition motif. Structural modifications of the RGDS lead have led to the discovery of a non-peptide RGD mimetic GP IIb/IIIa antagonist 44 (S 1197). Compound 44 inhibited, in a dose dependent and reversible manner, human and dog platelet aggregation as well as 125I-fibrinogen binding to ADP-activated human gel filtered platelets and isolated GP IIb/IIIa with K(i) values of 9 nM and 0.17 nM, respectively. A pharmacophore mapping procedure with QXP and a 3D-QSAR analysis applying the GRID/GOLPE methodology yielded a stable, rather predictive model and revealed structural features which are important for binding. Hydrophobic substitutions both at the hydantoin nucleus and at the C-terminus increase the affinity toward the fibrinogen receptor. The crystalline ethyl ester prodrug 48 (HMR 1794) is an orally active antithrombotic agent which is a promising drug candidate for the treatment of thrombotic diseases in humans.

RGD mimetics containing a central hydantoin scaffold: alpkha(v)beta3 vs alpha(IIb)beta3 selectivity requirements.

The synthesis of a series of RGD mimetic alpha(v)beta3 antagonists containing a hydantoin scaffold is shown. The results demonstrate some of the structural requirements for the design of selective alpha(v)beta3 antagonists (vs alpha(IIb)beta3) in terms of the Arg-mimetic, the distance between N- and C-terminus and the lipophilic side chain.