Linked Life Data

7799397

Source:http://linkedlifedata.com/resource/pubmed/id/7799397

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
26
pubmed:dateCreated
1995-1-26
pubmed:abstractText
Angiotensin II (AII), the endogenous peptide ligand of the AII receptor, has equivalent high affinity for both the AT1 and AT2 receptor subtypes while most of the reported nonpeptide AII antagonists are AT1-selective. In an effort to identify dual AT1/AT2 nonpeptide AII antagonists, we have pursued modifications of previously prepared trisubstituted 1,2,4-triazolinone biphenylsulfonamides which exhibited subnanomolar in vitro AT1 (rabbit aorta) AII antagonism and AT2 (rat midbrain) IC50 values of < 40 nM. Present results show that a suitable amide (or reversed amide) side chain appropriately positioned on the N2-aryl group of these compounds gave > 15-fold enhancement in AT2 binding affinity without sacrificing nanomolar AT1 potency (IC50). This added amide, combined with an appropriate choice of the N-substituent on the sulfonamide and the ortho substituent on the N2-aryl group, led to an analogue (46, L-163,-007) which exhibited subnanomolar AT1 binding affinity and an AT2/AT1 IC50 ratio of 3. This compound showed excellent iv activity at 1 mg/kg and oral efficacy at 3 mg/kg with > 6 h duration in a conscious rat model. Available data suggest that the newly introduced amide side chain, mandatory for low nanomolar binding affinity at the AT2 receptor, is well-tolerated by the AT1 receptor and has minimal effect on the in vivo properties of these molecules.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
23
pubmed:volume
37
pubmed:owner
NLM
pubmed:authorsComplete
N
pubmed:pagination
4464-78
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed:year
1994
pubmed:articleTitle
Triazolinone biphenylsulfonamides as angiotensin II receptor antagonists with high affinity for both the AT1 and AT2 subtypes.
pubmed:affiliation
Merck Research Laboratories, Rahway, New Jersey 07065.
pubmed:publicationType
Journal Article, In Vitro