Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 9 de 9
Filter
Add more filters










Database
Language
Publication year range
1.
Drug Chem Toxicol ; 36(3): 284-95, 2013 Jul.
Article in English | MEDLINE | ID: mdl-22947079

ABSTRACT

SHetA2 is a heteroarotinoid that has shown selective inhibition of cancer cell growth and an induction of apoptosis without activation of nuclear retinoic acid receptors. In the rat study, SHetA2 was administered in 1% aqueous methylcellulose/0.2% Tween 80 by oral gavage at 0, 100, 500, and 2,000 mg/kg/day for 28 days. The high-dose administration induced decreased activity in male rats, decreased body-weight gains and food consumption, and changes in organ weights. The major metabolite of SHetA2 in rat plasma was monohydroxy SHetA2, which was considerably higher than the parent compound after oral and intravenous administration. Pharmacokinetic analysis showed extremely low (<1%) systemic bioavailability of SHetA2 for all doses tested. The dose of 2,000 mg/kg/day was considered as the lowest observed adverse effect level. The no observed adverse effect level (NOAEL) was 500 mg/kg/day. In the dog study, no toxicity of SHetA2 in 30% aqueous Solutol(®) HS 15 was observed in any tested dose groups (0, 100, 400, and 1,500 mg/kg/day). The major metabolite of SHetA2 in dog plasma was also monohydroxy SHetA2, which was equal to or lower than the parent compound after oral administration. SHetA2 levels in dog plasma were notably higher, when compared to levels in rat plasma. However, exposure was not dose proportional, as exemplified by a lack of proportional increase in maximum concentration or area under the plasma concentration-time curve with increasing dose. The NOAEL was not established and was considered to be above 1,500 mg/kg/day.


Subject(s)
Anticarcinogenic Agents/pharmacokinetics , Anticarcinogenic Agents/toxicity , Chromans/pharmacokinetics , Chromans/toxicity , Thiones/pharmacokinetics , Thiones/toxicity , Administration, Oral , Adrenal Glands/drug effects , Adrenal Glands/pathology , Animals , Anticarcinogenic Agents/administration & dosage , Area Under Curve , Chromans/administration & dosage , Dogs , Eating/drug effects , Female , Male , Motor Activity/drug effects , No-Observed-Adverse-Effect Level , Organ Size/drug effects , Prostate/drug effects , Prostate/pathology , Rats , Rats, Sprague-Dawley , Species Specificity , Thiones/administration & dosage , Toxicity Tests , Weight Gain/drug effects
2.
Bioorg Med Chem Lett ; 20(8): 2658-64, 2010 Apr 15.
Article in English | MEDLINE | ID: mdl-20303752

ABSTRACT

A series of novel 1,7-disubstituted oxyindoles were shown to be potent and selective EP(3) receptor antagonists. Variation of substitution pattern at the C-3 position of indole enhanced in vitro metabolic stability of the resulting derivatives. Series 27a-c showed >1000-fold selectivity over a panel of prostanoid receptors including IP, FP, EP(1), EP(2) and EP(4). These agents also featured low CYP inhibition and good activity in the functional rat platelet aggregation assay.


Subject(s)
Indoles/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/drug effects , Receptors, Prostaglandin E/antagonists & inhibitors , Animals , Indoles/chemistry , Platelet Aggregation Inhibitors/chemistry , Rats , Receptors, Prostaglandin E, EP3 Subtype
3.
J Med Chem ; 53(1): 18-36, 2010 Jan 14.
Article in English | MEDLINE | ID: mdl-19957930

ABSTRACT

The EP(3) receptor on the platelet mediates prostaglandin E(2) potentiation of thrombogenic coagonists including collagen and adenosine diphosphate (ADP). A pharmacophore driven approach led to the identification of diverse peri-substituted heterocycles as potent and selective EP(3) receptor antagonists. A simultaneous chemical optimization and druglike assessment of prioritized molecules converged on a lead compound 50 (DG-041) that displayed favorable in vitro and functional activities as an inhibitor of human platelet aggregation. This agent is currently in human clinical trials for the treatment of atherothrombosis.


Subject(s)
Acrylamides/pharmacology , Hemorrhage , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/drug effects , Receptors, Prostaglandin E/antagonists & inhibitors , Sulfones/pharmacology , Acrylamides/chemical synthesis , Acrylamides/chemistry , Blood Coagulation/drug effects , Drug Discovery , Humans , Ligands , Molecular Structure , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Aggregation Inhibitors/chemistry , Receptors, Prostaglandin E, EP3 Subtype , Stereoisomerism , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/chemistry
4.
J Med Chem ; 53(2): 573-85, 2010 Jan 28.
Article in English | MEDLINE | ID: mdl-19950900

ABSTRACT

Both in-house human genetic and literature data have converged on the identification of leukotriene 4 hydrolase (LTA(4)H) as a key target for the treatment of cardiovascular disease. We combined fragment-based crystallography screening with an iterative medicinal chemistry effort to optimize inhibitors of LTA(4)H. Ligand efficiency was followed throughout our structure-activity studies. As applied within the context of LTA(4)H inhibitor design, the chemistry team was able to design a potent compound 20 (DG-051) (K(d) = 26 nM) with high aqueous solubility (>30 mg/mL) and high oral bioavailability (>80% across species) that is currently undergoing clinical evaluation for the treatment of myocardial infarction and stroke. The structural biology-chemistry interaction described in this paper provides a sound alternative to conventional screening techniques. This is the first example of a gene-to-clinic paradigm enabled by a fragment-based drug discovery effort.


Subject(s)
Butyrates/pharmacology , Cardiovascular Diseases/drug therapy , Drug Discovery/methods , Epoxide Hydrolases/antagonists & inhibitors , Heterocyclic Compounds/pharmacology , Biological Availability , Butyrates/chemistry , Butyrates/therapeutic use , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Epoxide Hydrolases/biosynthesis , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/therapeutic use , Humans , Ligands , Myocardial Infarction/drug therapy , Peptide Fragments/chemistry , Solubility , Stroke/drug therapy , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 19(22): 6275-9, 2009 Nov 15.
Article in English | MEDLINE | ID: mdl-19819140

ABSTRACT

The same two major CYP mediated metabolites of DG-051 were produced in the presence of rat, dog, monkey and human liver microsomes. Their respective structures were hypothesized based on mass spectrometry data correlated with the parent structure and confirmed by comparison with authentic synthetic samples. The number of regioisomers synthesized as candidates for metabolite M1 was narrowed down using a metabolic study of a selectively deuterated DG-051 analogue.


Subject(s)
Enzyme Inhibitors/chemistry , Epoxide Hydrolases/antagonists & inhibitors , Microsomes, Liver/metabolism , Spectrophotometry, Ultraviolet/methods , Anesthetics, Dissociative , Animals , Chromatography, High Pressure Liquid , Cytochrome P-450 CYP3A/metabolism , Dogs , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Mass Spectrometry/methods , Metabolomics , Molecular Structure , Rats , Small Molecule Libraries , Spectrometry, Mass, Electrospray Ionization/methods , Tandem Mass Spectrometry/methods
6.
ACS Chem Biol ; 4(2): 115-26, 2009 Feb 20.
Article in English | MEDLINE | ID: mdl-19193156

ABSTRACT

Myocardial infarction and stroke are caused by blood clots forming over a ruptured or denuded atherosclerotic plaque (atherothrombosis). Production of prostaglandin E(2) (PGE(2)) by an inflamed plaque exacerbates atherothrombosis and may limit the effectiveness of current therapeutics. Platelets express multiple G-protein coupled receptors, including receptors for ADP and PGE(2). ADP can mobilize Ca(2+) and through the P(2)Y(12) receptor can inhibit cAMP production, causing platelet activation and aggregation. Clopidogrel (Plavix), a selective P(2)Y(12) antagonist, prevents platelets from clotting but thereby increases the risk of severe or fatal bleeding. The platelet EP(3) receptor for PGE(2), like the P(2)Y(12) receptor, also inhibits cAMP synthesis. However, unlike ADP, facilitation of platelet aggregation via the PGE(2)/EP(3) pathway is dependent on co-agonists that can mobilize Ca(2+). We used a ligand-based design strategy to develop peri-substituted bicylic acylsulfonamides as potent and selective EP(3) antagonists. We show that DG-041, a selective EP(3) antagonist, inhibits PGE(2) facilitation of platelet aggregation in vitro and ex vivo. PGE(2) can resensitize platelets to agonist even when the P(2)Y(12) receptor has been blocked by clopidogrel, and this can be inhibited by DG-041. Unlike clopidogrel, DG-041 does not affect bleeding time in rats, nor is bleeding time further increased when DG-041 is co-administered with clopidogrel. This indicates that EP(3) antagonists potentially have a superior safety profile compared to P(2)Y(12) antagonists and represent a novel class of antiplatelet agents.


Subject(s)
Acrylamides/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/drug effects , Prostaglandin Antagonists/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Sulfones/pharmacology , Animals , Clopidogrel , Dinoprostone/antagonists & inhibitors , Dinoprostone/metabolism , Female , Hemorrhage/prevention & control , Humans , Male , Platelet Aggregation Inhibitors/chemistry , Purinergic P2 Receptor Antagonists , Rats , Receptors, Prostaglandin E, EP3 Subtype , Receptors, Purinergic P2Y12 , Thrombosis/drug therapy , Thrombosis/metabolism , Ticlopidine/analogs & derivatives , Ticlopidine/pharmacology
7.
Bioorg Med Chem Lett ; 19(5): 1528-31, 2009 Mar 01.
Article in English | MEDLINE | ID: mdl-19188065

ABSTRACT

A series of potent and selective EP(3) receptor antagonists are described. Utilizing a pharmacophore model developed for the EP(3) receptor, a series of 3,4-disubstituted indoles were found to be efficient ligands for this target. These compounds showed high selectivity over IP, FP and other EP receptors. An optimized molecule 7c featured a sound profile and potency in the functional rat and human platelet aggregation assays.


Subject(s)
Acrylamides/chemical synthesis , Acrylamides/metabolism , Indoles/chemical synthesis , Indoles/metabolism , Receptors, Prostaglandin E/antagonists & inhibitors , Acrylamides/pharmacology , Animals , CHO Cells , Cricetinae , Cricetulus , Dogs , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Drug Stability , Haplorhini , Humans , Indoles/pharmacology , Mice , Rats , Receptors, Prostaglandin E/metabolism , Receptors, Prostaglandin E, EP3 Subtype
8.
Bioorg Med Chem Lett ; 19(1): 123-6, 2009 Jan 01.
Article in English | MEDLINE | ID: mdl-19022669

ABSTRACT

A series of potent and selective EP(3) receptor antagonists are described. Utilizing a pharmacophore model developed for the EP(3) receptor, a series of 3,4-disubstituted indoles were shown to be high affinity ligands for this target. These compounds showed high selectivity over IP, FP and other EP receptors and are potent antagonists in functional assays.


Subject(s)
Receptors, Prostaglandin E/antagonists & inhibitors , Sulfonamides/chemical synthesis , Humans , Indoles , Ligands , Receptors, Prostaglandin E, EP3 Subtype , Structure-Activity Relationship , Sulfonamides/pharmacology
9.
Curr Protoc Pharmacol ; Chapter 7: Unit 7.9, 2004 Oct 01.
Article in English | MEDLINE | ID: mdl-22294125

ABSTRACT

The isolated perfused rat liver (IPRL) has been extensively used as an intact organ model for determination of hepatic clearance and metabolism of drugs. The IPRL model can also be applied to determine physiologically based pharmacokinetics. Since the IPRL model avoids neural and hormonal interferences and excludes influences from absorption processes and non-hepatic elimination routes such as renal excretion and respiration, it provides a relatively clean hepatic system to study metabolism and pharmacokinetics. It is especially useful to model the hepatic uptake associated with plasma protein binding and transport. The viability of the liver can be evaluated based on the gross appearance, bile flow, perfusion pressure, lactate dehydrogenase release, and oxygen uptake. The protocol describes the surgical procedures for isolation of the rat liver, a hemoglobin-free perfusion method, and application of this model for determination of hepatic uptake and clearance.


Subject(s)
Liver/metabolism , Pharmaceutical Preparations/metabolism , Animals , Bile/physiology , Cholagogues and Choleretics/pharmacokinetics , In Vitro Techniques , L-Lactate Dehydrogenase/metabolism , Ligation , Liver/surgery , Male , Oxygen/analysis , Perfusion , Rats , Rats, Sprague-Dawley , Specimen Handling/methods , Taurocholic Acid/pharmacokinetics , Tissue Survival/physiology
SELECTION OF CITATIONS
SEARCH DETAIL
...