DESIGN OF A POTENT COMBINED PSEUDOPEPTIDE ENDOTHELIN-A ENDOTHELIN-B RECEPTOR ANTAGONIST, AC-DBHG(16)-LEU-ASP-ILE-[NME]ILE-TRP(21) (PD-156252) - EXAMINATION OF ITS PHARMACOKINETIC AND SPECTRAL PROPERTIES/

The endothelins (ETs) are a family of bicyclic 21-amino acid peptides that are potent and prolonged vasoconstrictors. It has been shown that highly potent combined ETA/ETB receptor antagonists can be developed from the C-terminal hexapeptide of ET (His(16)-Leu(17)-Asp(18)-Ile(19) -Ile(20)-Trp(21)), such as Ac-DDip(16)-Leu-Asp-Ile-Ile-Trp(21) (PD 142 893) and Ac-DBhg(16)-Leu-Asp-Ile-Ile-Trp(21) (PD 145065). However, the se compounds are relatively unstable to enzymatic proteolysis as deter mined in an in vitro rat intestinal perfusate assay. This instability is thought to be due to carboxypeptidase activity. In fact, incubation of PD 145065 with carboxypeptidase inhibitors greatly increased its h alf-life in rat intestinal perfusate. By performing a reduced amide bo nd and N-methyl amino acid scan, it was discovered that N-methylation of Ile(20) resulted in a compound (Ac-DBhg(16)-Leu-Asp-Ile-[NMe]Ile-Tr p(21), PD 156252) that retained full receptor affinity at both endothe lin receptor subtypes along with enhanced proteolytic stability and ce llular permeability. Interestingly, N-methylation of this bond allows the cis configuration to be readily accessible which greatly alters th e preferred structure of the entire molecule and may be responsible fo r the observed enhanced metabolic stability.