STRUCTURE-ACTIVITY-RELATIONSHIPS OF A NOVEL SERIES OF ORALLY-ACTIVE NONPEPTIDE ET(A) AND ET(A B) ENDOTHELIN RECEPTOR-SELECTIVE ANTAGONISTS/

The development of nonpeptide, low molecular weight antagonists with h igh potency, oral activity, and selectivity is an important objective to adequately define the potential role of endothelin (ET) and its iso peptides in human diseases. This report describes the structure-activi ty relationships, ET(A)/ET(B) selectivity, and pharmacokinetics of the PD 155080 and PD 156707 series of orally active nonpeptide ET recepto r-selective antagonists. Modification of the substituents around the b utenolide ring has led to compounds with differing selectivity for hum an ET(A) and ET(B) receptors. Thus, compounds with increased lipophili city at R(2) show increased ET(B) affinity and a more balanced ET(A)/E T(B) profile. For example, the 4-O-n-pentyl analogue of PD 156707 is a potent competitive inhibitor of [I-125]ET-1 and [I-125]ET-3 binding t o human cloned ET(A) and ET(B) receptors, with IC(50)s of 0.8 nM and 4 4 nM, respectively. Pharmacokinetic properties can also be significant ly influenced by structural modifications at the R(2) group. The pharm acokinetics of PD 155719, PD 155080, and PD 156707 were compared in ma le Wistar rats after a 15 mg/kg intravenous or oral gavage dose (three animals per dose). Plasma concentrations were determined by a specifi c HPLC assay. Oral bioavailability ranged from less than 5% for PD 155 719 to 41% for PD 156707 and 87% for PD 155080.