The design of potent hexapeptide endothelin antagonists stable to proteolysis

Cody, Wayne L.; He, John X.; Doherty, Annette M.; DePue, Patricia L.; Kaltenbronn, J. S.; Reisdorph, B. R.; Walker, Donnelle M.; Welch, Kathleen M.; Haleen, Stephen J.; Reynolds, Elwood E.; E, Tse; Reyner, Eric L.; Stewart, Barbra H.

doi:10.1007/978-94-011-1468-4_10

Cited by 1 publication

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“…Given that an aromatic amino acid is at the C-terminus of the peptide, this provided evidence of the involvement of carboxypeptidase A which prefers this substrate configuration . In addition, it was shown by reversed-phase high-performance liquid chromatography, as well as mass spectrometry, that Ac- d Dip 16 -Leu-Asp-Ile-Ile and Ac- d Bhg 16 -Leu-Asp-Ile-Ile were the primary metabolites of compounds 2 and 3 , respectively. , …”

Section: Resultsmentioning

confidence: 99%

“…Similar to the reduced amide bond analogues, most of the N-methylated analogues of compound 2 (compounds 9 − 12 and 14 ; Table ) showed losses in receptor affinity of 7−160-fold. However, Ac- d Dip 16 -Leu-Asp-Ile-[NMe]Ile-Trp 21 (compound 13) maintained high affinity for both the ET A and ET B receptor subtypes (30 and 80 nM, respectively) …”

Section: Resultsmentioning

confidence: 99%

“…Likewise, compound 15 was able to antagonize ET-1-stimulated vasoconstriction in vitro in the rabbit femoral artery (ET A , p A 2 = 7.3) and SRTX-6c-stimulated vasoconstriction in the rabbit pulmonary artery (ET B , p A 2 = 6.6). Thus, compound 15 represents a highly potent combined ET A and ET B receptor antagonist (Figure ) 2 Structure of compound 15 (PD 156252). …”

Section: Resultsmentioning

confidence: 99%

“…In designing these antagonists the importance of the following structural features were considered: (i) the neutralization of the amine terminus by acetylation enhanced activity ∼10-fold, (ii) the preference for d -aromatic amino acids in the 16 position, (iii) the requirement for a tryptophan of the l -stereochemistry in the C-terminal 21 position, and (iv) the necessity of a C-terminal carboxylate. − These observations resulted in the design and preparation of Ac- d Dip 16 -Leu-Asp-Ile-Ile-Trp 21 [compound 2 , PD 142893 (Dip = 3,3-diphenylalanine)] ,− and Ac- d Bhg 16 -Leu-Asp-Ile-Ile-Trp 21 [PD 145065, compound 3 (Bhg = 10,11-dihydro-5 H -dibenzo[ a,d ]cycloheptene-glycine)]. − Both of these compounds exhibited low-nanomolar affinity for the ET A (58 and 4.0 nM, respectively) and ET B (130 and 30 nM, respectively) receptors. Likewise, compounds 2 and 3 were able to antagonize ET-1-stimulated vasoconstriction in vitro in the rabbit femoral artery (ET A , p A 2 = 6.6 and 6.8, respectively) and SRTX-6c-stimulated vasoconstriction in the rabbit pulmonary artery (ET B , p A 2 = 6.3 and 7.0, respectively). ,− Unfortunately, both of these compounds have relatively short half-lives (18.1 ± 3.4 and 10.6 ± 2.2 min, respectively) in rat intestinal perfusate, suggesting limited utility of these compounds for further in vivo evaluation. , …”

Section: Introductionmentioning

confidence: 99%

“…( 3.4 and 10.6 ( 2.2 min, respectively) in rat intestinal perfusate, suggesting limited utility of these compounds for further in vivo evaluation. 33,34 In an attempt to further stabilize these compounds against proteolytic degradation while maintaining receptor affinity, a reduced amide bond and N-methylated amino acid scan of compound 2 was performed. These modifications, in particular the incorporation of Nmethylated amino acids, should have significant effects on the conformational preferences of the peptide backbone.…”

Section: Introductionmentioning

confidence: 99%

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Design of a Potent Combined Pseudopeptide Endothelin-A/Endothelin-B Receptor Antagonist, Ac-dBhg¹⁶-Leu-Asp-Ile-[NMe]Ile-Trp²¹(PD 156252): Examination of Its Pharmacokinetic and Spectral Properties

Cody¹,

He²,

Reily³

et al. 1997

J. Med. Chem.

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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 (His16-Leu17-Asp18-Ile19-Ile20-Trp21), such as Ac-(D)Dip16-Leu-Asp-Ile-Ile-Trp21 (PD 142893) and Ac-DBhg16-Leu-Asp-Ile-Ile-Trp21 (PD 145065). However, these compounds are relatively unstable to enzymatic proteolysis as determined 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 half-life in rat intestinal perfusate. By performing a reduced amide bond and N-methyl amino acid scan, it was discovered that N-methylation of Ile-20 resulted in a compound (Ac-DBhg16-Leu-Asp-Ile-[NMe]Ile-Trp21, PD 156252) that retained full receptor affinity at both endothelin receptor subtypes along with enhanced proteolytic stability and cellular permeability. Interestingly, N-methylation of this bond allows the cis configuration to be readily accessible which greatly alters the preferred structure of the entire molecule and may be responsible for the observed enhanced metabolic stability.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%