Subject(s)
Integrin alpha4/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Precursor Cells, B-Lymphoid/drug effects , Thiophenes/chemistry , Urea/analogs & derivatives , Animals , Antineoplastic Agents/chemistry , Coculture Techniques , Drug Resistance, Neoplasm , Humans , Inflammation , Leukemia/drug therapy , Mice , Neoplasm Transplantation , Precursor Cells, B-Lymphoid/cytology , Stromal Cells/cytology , Thiophenes/administration & dosage , Urea/administration & dosage , Urea/chemistryABSTRACT
We have previously disclosed the discovery of 2,4-disubstituted anilinothiophenesulfonamides with potent ET(A)-selective endothelin receptor antagonism and the subsequent identification of sitaxsentan (TBC11251, 1) as a clinical development compound (Wu et al. J. Med. Chem. 1997, 40, 1682 and 1690). The orally active 1 has demonstrated efficacy in a phase II clinical trial of congestive heart failure (Givertz et al. Circulation 1998, 98, Abstr. #3044) and was active in rat models of myocardial infarction (Podesser et al. Circulation 1998, 98, Abstr. #2896) and acute hypoxia-induced pulmonary hypertension (Chen et al. FASEB J. 1996, 10 (3), A104). We now report that an additional substituent at the 6-position of the anilino ring further increases the potency of this series of compounds. It was also found that a wide range of functionalities at the 3-position of the 2,4,6-trisubstituted ring increased ET(A) selectivity by approximately 10-fold while maintaining in vitro potency, therefore rendering the compounds amenable to fine-tuning of pharmacological and toxicological profiles with enhanced selectivity. The optimal compound in this series was found to be TBC2576 (7u), which has approximately 10-fold higher ET(A) binding affinity than 1, high ET(A)/ET(B) selectivity, and a serum half-life of 7.3 h in rats, as well as in vivo activity.
Subject(s)
Endothelin Receptor Antagonists , Sulfonamides/chemical synthesis , Thiophenes/chemical synthesis , Administration, Oral , Animals , Biological Availability , Drug Evaluation, Preclinical , Half-Life , Hypertension, Pulmonary/blood , Hypertension, Pulmonary/metabolism , Models, Molecular , Rats , Rats, Sprague-Dawley , Receptor, Endothelin A , Receptors, Endothelin/metabolism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/metabolism , Sulfonamides/pharmacology , Thiophenes/chemistry , Thiophenes/metabolism , Thiophenes/pharmacologyABSTRACT
Vascular hyperpermeability and excessive neovascularization are hallmarks of early and late vascular endothelial cell dysfunction induced by diabetes. Vascular endothelial growth factor (VEGF) appears to be an important mediator for these early and late vascular changes. We reported previously, using skin chambers mounted on backs of SD rats, that neutralizing antibodies directed against VEGF blocked vascular permeability and blood flow changes induced by elevated tissue glucose and sorbitol levels in a dosage-dependent manner. We report in this study, using the same skin chamber model and neutralizing antibodies directed against basic fibroblast growth factor (FGF-2), that another member of the heparin-binding growth factor family also mediates glucose- and sorbitol-induced vascular permeability and blood flow increases. In addition, we show that 1) TBC1635, a novel heparin-binding growth factor antagonist, blocks the vascular hyperpermeability and blood flow increases induced by elevated tissue levels of glucose and sorbitol and by topical application of VEGF and FGF-2 to granulation tissue in skin chambers, and 2) suramin, a commercially available growth factor antagonist, blocks glucose-induced vascular dysfunction. These results suggest an early role for heparin-binding growth factors in the vascular dysfunction caused by excessive glucose metabolism, possibly via the sorbitol pathway.
