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Biomedical subjects

B E Evans

Publications and source records attributed to B E Evans.

At least 19 recordsLinked to original sources
PubMed1994

1-((7,7-Dimethyl-2(S)-(2(S)-amino-4-(methylsulfonyl)butyramido)bicyclo [2.2.1]-heptan-1(S)-yl)methyl)sulfonyl)-4-(2-methylphenyl)piperaz ine (L-368,899): an orally bioavailable, non-peptide oxytocin antagonist with potential utility for managing preterm labor.

Modifications to the previously reported spiroindenylpiperidine camphor-sulfonamide oxytocin (OT) antagonist L-366,509 have produced a new series of o-tolylpiperazine (TP) camphor-sulfonamides. A number of analogues in the TP series that incorporate a modified or unmodified L-methionine sulfone amide at the C2 endo position on the camphor ring exhibit high affinity for OT receptors (IC50 = 1.3-15 nM) and good selectivity for binding to OT versus arginine vasopressin V1a and V2 receptors. Several of these analogues were additionally characterized as potent antagonists of OT-stimulated contractions of the isolated and/or in situ rat uterus. Compound 7 (L-368,899) exhibited the best overall profile of OT receptor affinity (IC50 = 8.9 nM, rat uterus; 26 nM, human uterus), potency for inhibition of OT-stimulated contractions of the isolated rat uterus (pA2 = 8.9) and in situ rat uterus (AD50 = 0.35 mg/kg after intravenous (i.v.) administration and 7.0 mg/kg after intraduodenal administration), aqueous solubility (3.7 mg/mL at pH 5.0), and oral bioavailability in several species (35% (rat), 25% (dog), and 21% (chimpanzee) as estimated from radioreceptor determination of drug levels in plasma after oral and i.v. dosing). On the basis of these favorable properties, 7 has begun clinical testing for use as an oral and i.v. tocolytic agent. Molecular modeling alignment studies have provided support for the hypothesis that the TP camphor-sulfonamide portion of the non-peptide structures may serve as a mimetic of the important D-AA2-Ile3 dipeptide (AA = aromatic amino acid) found in many potent OT antagonists from the cyclic hexapeptide and OT analogue structural classes.

Animals↗
PubMed1992

Orally active, nonpeptide oxytocin antagonists.

The first nonpeptide antagonists of the neurohypophyseal hormone, oxytocin (OT) are described. Derivatives of the spiroindenepiperidine ring system, these compounds include L-366,509, an orally bioavailable OT antagonist with good in vivo duration. The potential use of these agents for treatment of preterm labor and their significance as new nonpeptide ligands for peptide receptors are discussed.

Administration, Oral↗
PubMed1991

Vulvar vestibulitis syndrome: a clinico-pathological study.

Twenty four patients with the vulvar vestibulitis syndrome formed the basis of this clinicopathological study. Entry dyspareunia was the constant presenting complaint and vestibular erythema with acute superficial tenderness the invariable clinical finding. In our series there was a marked predominance of Caucasians, patients were most often of social classes I and II and most frequently in the third decade. The results of laboratory investigation revealed that this syndrome has a diverse range of potential aetiologies including vulval infections, dysplasia and in one instance acute vasculitis.

Age Factors↗
PubMed1991

Molecular design of potent specific antagonists for the gastrin and cholecystokinin receptors.

Widespread distribution of receptors for the peptide hormones cholecystokinin (CCK) and gastrin in the gut and in the CNS suggests therapeutic potential for selective antagonists of these hormones. Discovery of the natural product Asperlicin provided a new class of non-peptidal CCK antagonists, but oral bioavailability in this class remained elusive. With Asperlicin as a guide, the new, selective, orally bioavailable, high affinity CCK-A antagonist, MK-329 (L-364,718; Devazepide) and CCK-B/gastrin antagonist, L-365,260 have been developed. Biological profiles of these compounds are presented and results of early clinical evaluation of MK-329 are described. The significance of these agents as models for development of non-peptidal ligands for other receptors are briefly summarized.

Animals↗
PubMed1990

Cholecystokinin-A receptor ligands based on the kappa-opioid agonist tifluadom.

Tifluadom, a kappa-opioid agonist and cholecystokinin-A (CCK-A) receptor antagonist, was utilized as a model to prepare a series of 2-(aminomethyl)- and 3-(aminomethyl)-1,4-benzodiazepines. These compounds were tested in vitro as inhibitors of the binding of [125I]CCK to rat pancreas and guinea pig brain receptors. All compounds with IC50's less than 100 microM proved to have greater affinity for the CCK-A receptor, with the most potent analogue, 6e, having an IC50 of 0.16 microM. The benzodiazepines described in this study are simultaneously CCK-A and opioid receptor ligands. The ramification of this dichotomy on current concepts of peptide hormone action are discussed. These results further demonstrate the versatility of the benzodiazepine core structure for designing nonpeptide ligands for peptide receptors and the ability to fine-tune the receptor interactions of these benzodiazepines by appropriate structure modifications.

Animals↗
PubMed1988

Renin inhibitors containing hydrophilic groups. Tetrapeptides with enhanced aqueous solubility and nanomolar potency.

Nineteen tetrapeptides containing statine (Sta) and 4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA) were prepared. Solubility measurements of these compounds were carried out in H2O and in pH 7.4 phosphate buffer solution, and their partition coefficients were determined in a 1:1 1-octanol/sodium phosphate-citric acid buffer system. The tetrapeptides were tested in vitro for their ability to inhibit porcine, canine, and human plasma renins. Four compounds, 6, 12, 14, and 20, were potent inhibitors against all renins tested (IC50 = 10(-9) M). Compound 12 was administered orally to dogs and substantially inhibited plasma renin activity for up to 5 h. The addition of polar groups to the C-terminus of Sta- and ACHPA-containing tetrapeptides renders them soluble in aqueous milieu and provides a valuable tool with which to examine the role of the renin-angiotensin system in physiological and pathological circumstances.

Amino Acids↗
PubMed1988

Methods for drug discovery: development of potent, selective, orally effective cholecystokinin antagonists.

3-(Acylamino)-5-phenyl-2H-1,4-benzodiazepines, antagonists of the peptide hormone cholecystokinin (CCK), are described. Developed by reasoned modification of the known anxiolytic benzodiazepines, these compounds provide highly potent, orally effective ligands selective for peripheral (CCK-A) receptors, with binding affinities approaching or equaling that of the natural ligand CCK-8. The distinction between CCK-A receptors on the one hand and CNS (CCK-B), gastrin, and central benzodiazepine receptors on the other is demonstrated by using the structure-activity profiles of the new compounds. Details of the binding of these agents to CCK-A receptors are examined, and the method of development of these compounds is discussed in terms of its relevance to the general problem of drug discovery.

Administration, Oral↗
PubMed1988

Cholecystokinin antagonists. Synthesis and biological evaluation of 4-substituted 4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepines.

A series of 4-substituted 4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepines was prepared by standard methodology. These compounds were tested in vitro as antagonists of the binding of [125I]cholecystokinin (CCK) to rat pancreas and guinea pig brain receptors and of the binding of [125I]gastrin to guinea pig gastric glands. All compounds proved to have greater affinity for the peripheral CCK receptor with some analogues having IC50's in the subnanomolar range. In vivo activity of selected compounds in mice is presented and the structure/activity profile of this class of benzodiazepines as CCK antagonists is discussed.

Animals↗
PubMed1987

Design of nonpeptidal ligands for a peptide receptor: cholecystokinin antagonists.

A series of 3-substituted 5-phenyl-1,4-benzodiazepines, nonpeptidal antagonists of the peptide hormone cholecystokinin (CCK), have been synthesized. Designed on the basis of facts regarding CCK, its natural-product antagonist asperlicin (3), and the antianxiety agent diazepam (4), these compounds represent a significant departure from existing CCK antagonists. They also constitute perhaps the first examples of simple, nonpeptidal ligands for a peptide receptor to arise by design rather than by screening. These compounds serve to illuminate the distinction between central and peripheral CCK receptors, as well as to provide orally effective CCK antagonists of potential pharmacological or therapeutic utility. One rationale for their receptor affinity has possible applications in the design of nonpeptidal ligands for other receptors, peptidal as well as nonpeptidal.

Animals↗
PubMed1987

Renin inhibitors. Statine-containing tetrapeptides with varied hydrophobic carboxy termini.

A series of statine-containing tetrapeptides, systematically modified at the carboxy terminus with various hydrophobic aromatic groups, is described. These compounds were tested in vitro for their ability to inhibit porcine, human plasma, and purified human kidney renins. These analogues help to define optimal binding aspects in a region of the enzyme that appears to be specific for spatial arrangement of aromatic groups. Replacement of the metabolically labile Phe amide with nonpeptidal groups proved possible while achieving inhibitory potency in the nanomolar range vs. porcine kidney renin. For the compounds 6i, 6m, and 6o, a large discrepancy in potency between the human plasma and the purified human kidney renin assays was observed. This disparity does not appear to be a consequence of a previously proposed plasma binding component.

Amino Acids↗
PubMed1986

3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. 2. Structural modification of 7-(substituted aryl)-3,5-dihydroxy-6-heptenoic acids and their lactone derivatives.

A series of 7-(substituted aryl)-3,5-dihydroxy-6-heptenoic (heptanoic) acids and their lactone derivatives have been prepared and tested for inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in vitro. A systematic exploration of the structure-activity relationships in this series led to the synthesis of (+)-trans-(E)-6-[2-[2,4-dichloro-6-[(4-fluorophenyl) methoxyl]phenyl]ethyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (66(+)), which has one-half of the inhibitory activity of compactin.

Animals↗
PubMed1986

Cholecystokinin antagonists. Synthesis of asperlicin analogues with improved potency and water solubility.

Seventeen analogues of the selective, competitive cholecystokinin (CCK) antagonist asperlicin 1 were prepared. These compounds were tested as inhibitors of the binding of [125I]CCK to rat pancreas and guinea pig brain receptors. Compounds 4, 7, and 8 were more potent than asperlicin on the pancreatic CCK receptor. One analogue, 17, displayed potency equivalent to asperlicin on the pancreas CCK receptor and showed a marked improvement in aqueous solubility, thereby facilitating the use of this class of CCK antagonists in physiological and pharmacological studies.

Animals↗
PubMed1986

Design of potent, orally effective, nonpeptidal antagonists of the peptide hormone cholecystokinin.

We describe the design and synthesis of nonpeptidal antagonists of the peptide hormone cholecystokinin. Several of these compounds have high specificity and nanomolar binding affinity and are active after oral administration. To our knowledge, the design of such agents has not previously been accomplished for any peptide hormone. The structural similarities between these synthetic compounds and the anxiolytic 1,4-benzodiazepines are noted, and the potential of this structural feature for future design of ligands for other peptide hormone receptors is discussed.

Animals↗
PubMed1986

AIDS concerns.

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Acquired Immunodeficiency Syndrome↗