Linked Life Data

8786709

Source:http://linkedlifedata.com/resource/pubmed/id/8786709

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
1996-9-20
pubmed:abstractText
Endothelin (ET-1) is a 21-amino acid, vasoconstrictive peptide originally isolated from endothelial cells. It is one member of a class of potent, purportedly paracrine substances that act at receptors in multiple target organs. Antagonists to the receptor subtypes, ETA and ETB, have been designed around the hydrophobic carboxy-terminus of ET-1. The resulting hexapeptides possess low nanomolar receptor affinity, but face formidable challenges to oral delivery, given their peptidic nature. Hence, it was important to discriminate between analogs, as well as to optimize structural features combining binding potency with stability in intestinal fluids and permeability across biological membranes. PD 142893 (Ac-DDip16-Leu-Asp-Ile-Trp21) and PD 145065 (Ac-DBhg16-Leu-Asp-Ile-Ile-Trp21), as well as the N-methyl-isoleucine20 analogs were studies, where DDip = 3,3diphenylalanine and DBhg = 10,11-dihydro-5H-dibenzo[a,d]cycloheptene glycine. Analyses were conducted with specific HPLC methods. Permeabilities across CACO-2 cell monolayers ranged from 2.0x10(-4) to 6.3x10(-4)cm/min. The results suggested that these compounds can be absorbed in vivo, based on comparison of permeabilities with those obtained with reference compounds. Much greater differences were observed between the analogs when stability half-lives were compared after incubation in rat intestinal perfusate. The parent peptides, PD 142893 and PD 145065, were unstable, with half-lives less than 20 min. N-Methylation of Ile20 resulted in large increases in stability half-lives to greater 500 min. Enzyme inhibition studies demonstrated the involvement of carboxypeptidase A in production of the primary metabolite, the des-Trp derivative. Identification of the primary metabolite of the parent peptide was made by differential UV scanning at 214/280 nm and mass spectral analyses.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
0024-3205
pubmed:author
pubmed:issnType
Print
pubmed:volume
58
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
971-82
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
1996
pubmed:articleTitle
In vitro assessment of oral delivery for hexapeptide endothelin antagonists.
pubmed:affiliation
Pharmacokinetics and Drug Metabolism Department, Parke-Davis Pharmaceutical Research, Warner-Lambert Company, Ann Arbor MI 48105 USA.
pubmed:publicationType
Journal Article, In Vitro