Structure-activity relationships of cyclic pentapeptide endothelin A receptor antagonists

Article abstract of DOI:10.1021/jm00021a021

Analogues of the natural product endothelin A (ET(A)) receptor antagonists cyclo(-D-Trp¹-D-Glu²-Ala³-D-Va1⁴-Leu⁵-) (1) and cyclo(-D-Trp¹-D-Glu²- Ala³-D-alloIle⁴-Leu⁵-) (2) were prepared and tested for inhibitory activity against [¹²⁵I]endothelin (ET-1) binding to protein ET(A) receptors. The DDLDL chirality sequence of the natural products appeared to be critical for inhibitory activity because conversion of either D-Trp or D- Glu (or both) in 1 to the corresponding L-isomer(s) abolished this property. Systematic modifications at each position of the natural products clarified the structure-activity relationships and led to highly potent and selective ET(A) receptor antagonists. Most replacements of D-Trp¹ and Leu⁵ with other amino acids caused a significant loss of inhibitory activity. In contrast, replacement of D-Glu² with D-Asp² enhanced the activity. With regard to the Ala³ position, all analogues with imino acids, independent of being cyclic or acyclic, showed higher affinities than did the amino acid analogues. In addition, most replacements with amino acids, which had various functional groups in their side chains, did not significantly modify ET(A) binding affinity. The D-Va1⁴/D-alloIle⁴ position was very important for inhibitory activity, and a β-position branched D-amino acid or a D-heteroarylglycine was preferable at this position. Among synthesized cyclic pentapeptides, compound 36 (BQ-518) was the most potent ETA receptor antagonist, with a pA₂ of 8.1 against ET-1-induced vasoconstriction in isolated porcine coronary arteries. This compound also showed the greatest selectivity between ET(A) and ET(B) receptors (IC₅₀ for human ET(A) = 1.2 nM, IC₅₀ for human ET(B) = 55 μM). In contrast, compound 8 (BQ-123) is a highly soluble, potent, and selective ET(A) receptor antagonist (pA₂ = 7.4, IC₅₀ for human ET(A) = 8.3 nM, IC₅₀ for human ET(B) = 61 μM). The sodium salt of 8 is practically freely soluble in saline. These compounds are useful tools for not only in vitro but also in vivo pharmacological studies.