An oral sphingosine 1-phosphate receptor 1 (S1P(1)) antagonist prodrug with efficacy in vivo: discovery, synthesis, and evaluation.

A prodrug approach to optimize the oral exposure of a series of sphingosine 1-phosphate receptor 1 (S1P(1)) antagonists for chronic efficacy studies led to the discovery of (S)-2-{[3'-(4-chloro-2,5-dimethylphenylsulfonylamino)-3,5-dimethylbiphenyl-4-carbonyl]methylamino}-4-dimethylaminobutyric acid methyl ester 14. Methyl ester prodrug 14 is hydrolyzed in vivo to the corresponding carboxylic acid 15, a potent and selective S1P(1) antagonist. Oral administration of the prodrug 14 induces sustained peripheral blood lymphocyte reduction in rats.

Effects of the novel protein kinase C inhibitor AEB071 (Sotrastaurin) on rat cardiac allograft survival using single agent treatment or combination therapy with cyclosporine, everolimus or FTY720.

NVP-AEB071 (AEB, sotrastaurin), an oral inhibitor of protein kinase C (PKC), effectively blocks T-cell activation. The immunosuppressive effects of oral AEB were demonstrated in a rat local graft versus host (GvH) reaction and rat cardiac transplantation models. T-cell activation was suppressed by 95% in blood from AEB-treated rats, with a positive correlation between T-cell inhibition and AEB blood concentration.

A monoselective sphingosine-1-phosphate receptor-1 agonist prevents allograft rejection in a stringent rat heart transplantation model.

FTY720 is an immunomodulator with demonstrated efficacy in a phase II trial of relapsing multiple sclerosis. FTY720-phosphate, the active metabolite generated upon phosphorylation in vivo, acts as a potent agonist on four of the five known sphingosine-1-phosphate (S1P(1)) receptors. AUY954, an aminocarboxylate analog of FTY720, is a low nanomolar, monoselective agonist of the S1P(1) receptor.

Macrophage infiltration detected at MR imaging in rat kidney allografts: early marker of chronic rejection?

Purpose: To evaluate detection of iron-loaded macrophages at magnetic resonance (MR) imaging as a noninvasive means to monitor early signs of chronic allograft rejection in the life-supporting Fisher-to-Lewis rat kidney transplantation model.

Materials And Methods: Experiments followed the Swiss federal regulations of animal protection. Male Fisher (n = 37) and Lewis (n = 77) rats were used.

Evaluation of biomarker discovery approaches to detect protein biomarkers of acute renal allograft rejection.

Management of host responses to allografts by immunosuppressive therapy is the cornerstone of transplantation medicine, but it is still deficient in one important element: biomarkers that are readily accessible and predict the fate of the transplant early, specifically, and reliably. Using a Brown Norway (BN)-to-Lewis rat renal allograft model of kidney transplantation, this study aims at evaluating two proteomic approaches to discover biomarkers for acute rejection: SELDI-MS technology and 2D gel electrophoresis combined with mass spectrometry. Several novel potential serum biomarkers have been identified for follow up.

Transplantation-induced functional/morphological changes in rat aorta allografts differ from those in arteries of rat kidney allografts.

The functional/morphological changes observed in rat aorta allografts were compared with those seen in the arteries of rat kidney allografts. Untreated allografts (F344-to-LEW) were collected at various times post-transplantation (Tx). Vascular smooth muscle cell (SMC) constriction to phenylephrine (Phe) and endothelial cell (EC)-dependent relaxation to acetylcholine (Ach) were assessed.

Mycophenolate sodium: tolerability and efficacy in transplantation in the rat.

Inhibition of inosine monophosphate dehydrogenase by mycophenolate compounds results in potent immunosuppression, as demonstrated by the efficacy of the marketed prodrug mycophenolate mofetil (MMF) in clinical allotransplantation. Side effects are well-known and include bone marrow depression and gastrointestinal intolerability. Mycophenolate sodium (MPS) is in clinical development as an enteric-coated formulation to alleviate this gastrointestinal adverse effect.