Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 112
Filter
6.
Bioorg Med Chem Lett ; 25(21): 4812-4819, 2015 Nov 01.
Article in English | MEDLINE | ID: mdl-26195137

ABSTRACT

The IC50 of a beta-secretase (BACE-1) lead compound was improved ∼200-fold from 11 µM to 55 nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pKa of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Hydantoins/chemistry , Hydantoins/pharmacology , Amyloid Precursor Protein Secretases/metabolism , Aspartic Acid Endopeptidases/metabolism , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Hydantoins/chemical synthesis , Methylation , Models, Molecular , Molecular Structure , Structure-Activity Relationship
7.
J Phys Condens Matter ; 23(8): 086005, 2011 Mar 02.
Article in English | MEDLINE | ID: mdl-21411908

ABSTRACT

The destruction of the ferromagnetism of alloyed SrRuO(3) can be caused by electron localization at the substitution sites. Among all the non-magnetic cations that enter the B site, Zr(4+) is the least disruptive to conductivity and ferromagnetism. This is because Zr(4+) does not cause any charge disorder, and its empty d electron states which are poorly matched in energy with the Ru t(2g)(4) states cause the least resonance scattering of Ru's d electrons. Conducting Sr(Ru, Zr)O(3) may be used as an electrode for perovskite-based thin film devices, while its insulating counterpart provides unprecedented magnetoresistance, seldom seen in other non-manganite and non-cobaltite perovskites.

8.
Circulation ; 117(16): 2096-103, 2008 Apr 22.
Article in English | MEDLINE | ID: mdl-18413497

ABSTRACT

BACKGROUND: Local drug delivery from polymer-coated stents has demonstrated efficacy for preventing in-stent restenosis; however, both the inflammatory effects of polymer coatings and concerns about late outcomes of drug-eluting stent use indicate the need to investigate innovative approaches, such as combining localized gene therapy with stent angioplasty. Thus, we investigated the hypothesis that adenoviral vectors (Ad) could be delivered from the bare-metal surfaces of stents with a synthetic complex for reversible vector binding. METHODS AND RESULTS: We synthesized the 3 components of a gene vector binding complex: (1) A polyallylamine bisphosphonate with latent thiol groups (PABT), (2) a polyethyleneimine (PEI) with pyridyldithio groups for amplification of attachment sites [PEI(PDT)], and (3) a bifunctional (amine- and thiol-reactive) cross-linker with a labile ester bond (HL). HL-modified Ad attached to PABT/PEI(PDT)-treated steel surfaces demonstrated both sustained release in vitro over 30 days and localized green fluorescent protein expression in rat arterial smooth muscle cell cultures, which were not sensitive to either inhibition by neutralizing anti-Ad antibodies or inactivation after storage at 37 degrees C. In rat carotid studies, deployment of steel stents configured with PABT/PEI(PDT)/HL-tethered adenoviral vectors demonstrated both site-specific arterial Ad(GFP) expression and adenovirus-luciferase transgene activity per optical imaging. Rat carotid stent delivery of adenovirus encoding inducible nitric oxide synthase resulted in significant inhibition of restenosis. CONCLUSIONS: Reversible immobilization of adenovirus vectors on the bare-metal surfaces of endovascular stents via a synthetic complex represents an efficient, tunable method for sustained release of gene vectors to the vasculature.


Subject(s)
Absorbable Implants , Carotid Stenosis/prevention & control , Carotid Stenosis/therapy , Gene Transfer Techniques , Genetic Therapy/methods , Stents , Adenoviridae/genetics , Animals , Aorta/cytology , Cells, Cultured , Cross-Linking Reagents , Green Fluorescent Proteins/genetics , Male , Metals , Muscle, Smooth, Vascular/cytology , Neutralization Tests , Nitric Oxide Synthase Type II/genetics , Rats , Rats, Sprague-Dawley , Secondary Prevention
9.
Xenobiotica ; 33(6): 643-54, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12851040

ABSTRACT

1. The use of a beneficial interaction between indinavir and compound A, a potent investigational HIV protease inhibitor to enhance systemic exposure of compound A, was investigated. 2. When administrated alone, compound A underwent extensive hepatic first-pass metabolism in rats and monkeys, resulting in low oral bioavailability. 3. In vitro studies with liver microsomes revealed that compound A metabolism was mediated exclusively by CYP3A enzymes in rats, dogs and monkeys. Indinavir, which also was metabolized predominantly by CYP3A enzymes, extensively inhibited compound A metabolism in microsomes, whereas compound A showed weak inhibitory potency on indinavir metabolism. 4. Consistent with in vitro observations, co-administration of the two compounds resulted in a 17-fold increase in oral AUC of compound A in rats owing to the inhibition of metabolism of compound A by indinavir, whereas compound A did not affect indinavir metabolism as indicated by the unchanged indinavir AUC. Similarly, the systemic exposure of compound A in dogs and monkeys was increased substantially following oral co-administration with indinavir by 7- and > 50-fold, respectively. 5. Enhancement in compound A systemic exposure by indinavir in humans, as predicted based on the in vivo animal and in vitro human liver microsomal data, was confirmed in subsequent clinical studies.


Subject(s)
Benzofurans/pharmacology , HIV Protease Inhibitors/pharmacology , HIV Protease Inhibitors/pharmacokinetics , Indinavir/analogs & derivatives , Indinavir/pharmacology , Piperazines/pharmacology , Animals , Antibodies, Blocking/pharmacology , Area Under Curve , Benzofurans/antagonists & inhibitors , Benzofurans/pharmacokinetics , Chromatography, High Pressure Liquid , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System , Dogs , Drug Synergism , Enzyme Inhibitors/pharmacology , HIV Protease Inhibitors/antagonists & inhibitors , Indinavir/antagonists & inhibitors , Indinavir/pharmacokinetics , Injections, Intravenous , Macaca mulatta , Male , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Piperazines/antagonists & inhibitors , Piperazines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Species Specificity , Spectrophotometry, Ultraviolet
10.
Drug Metab Dispos ; 29(12): 1578-87, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11717177

ABSTRACT

Compound I (1-(3-chlorophenyl)-4-[(1-(4-cyanobenzyl)-1H-imidazol-5-yl)methyl]piperazin-2-one) is a potent and selective inhibitor of farnesyl-protein transferase (FPTase). The pharmacokinetics and metabolism of compound I displayed species differences in rats and dogs. After oral administration, the drug was well absorbed in dogs but less so in rats. Following i.v. administration, compound I was cleared rapidly in rats in a polyphasic manner with a terminal t(1/2) of 41 min. The plasma clearance (CL(p)) and volume of distribution (V(dss)) were 41.2 ml/min/kg and 1.2 l/kg, respectively. About 1% of the dose was excreted in rat bile and urine as unchanged drug over a period of 24 h, suggesting that biotransformation is the major route of elimination of compound I. Using liquid chromatography (LC)-tandem mass spectometry, nineteen metabolites of compound I were identified in urine and bile from dogs and rats. Structures of two major metabolites were confirmed by LC-NMR. N-Dealkylation and phase II metabolism were the major metabolic pathways. Animal and human liver microsomal intrinsic clearance values were scaled to predict hepatic clearance and half-life in humans, and the predicted values were in good agreement to the in vivo data.


Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Imidazoles/pharmacology , Piperazines/pharmacology , Algorithms , Animals , Area Under Curve , Bile/metabolism , Bile Ducts/metabolism , Biotransformation , Blood Proteins/metabolism , Chromatography, High Pressure Liquid , Dogs , Farnesyltranstransferase , Half-Life , Humans , In Vitro Techniques , Intestinal Absorption , Male , Mass Spectrometry , Microsomes, Liver , Rats , Rats, Sprague-Dawley
11.
Bioorg Med Chem Lett ; 11(14): 1817-21, 2001 Jul 23.
Article in English | MEDLINE | ID: mdl-11459639

ABSTRACT

A series of amino acid-based linkers was used to investigate the effects of various substituents upon the potency, pharmacokinetic properties, and conformation of macrocyclic farnesyl-protein transferase inhibitors (FTIs). As a result of the studies described herein, highly potent FTIs with improved pharmacokinetic profiles have been identified.


Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Alkyl and Aryl Transferases/drug effects , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacokinetics , Amino Acids/chemistry , Animals , Cells, Cultured , Dogs , Enzyme Inhibitors/chemical synthesis , Half-Life , Inhibitory Concentration 50 , Metabolic Clearance Rate/physiology , Molecular Conformation , Protein Binding/drug effects , Rats
12.
Bioorg Med Chem Lett ; 11(4): 537-40, 2001 Feb 26.
Article in English | MEDLINE | ID: mdl-11229765

ABSTRACT

The evaluation of SAR associated with the insertion of carbonyl groups at various positions of N-arylpiperazinone farnesyltransferase inhibitors is described herein. 1-Aryl-2,3-diketopiperazine derivatives exhibited the best balance of potency and pharmacokinetic profile relative to the parent 1-aryl-2-piperazinones.


Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Piperazines/pharmacology , Animals , Dogs , Enzyme Inhibitors/pharmacokinetics , Farnesyltranstransferase , Structure-Activity Relationship
13.
Org Lett ; 2(22): 3473-6, 2000 Nov 02.
Article in English | MEDLINE | ID: mdl-11082012

ABSTRACT

[reaction: see text] Synthesis of the 8-amino-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine ring system was accomplished by intramolecular cyclization of an iminium ion, derived from condensation of an amine and a substituted gamma-(1-imidazolyl)butyraldehyde. The reaction was used to produce conformationally restricted farnesyltransferase inhibitor analogues which exhibit improved in vivo metabolic stability.


Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Imidazoles/chemical synthesis , Pyridines/chemical synthesis , Administration, Oral , Animals , Dogs , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Farnesyltranstransferase , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Indicators and Reagents , Models, Molecular , Molecular Conformation , Pyridines/chemistry , Pyridines/pharmacokinetics , Pyridines/pharmacology , Structure-Activity Relationship
14.
J Med Chem ; 43(18): 3386-99, 2000 Sep 07.
Article in English | MEDLINE | ID: mdl-10978186

ABSTRACT

Recent results from human clinical trials have established the critical role of HIV protease inhibitors in the treatment of acquired immune-deficiency syndrome (AIDS). However, the emergence of viral resistance, demanding treatment protocols, and adverse side effects have exposed the urgent need for a second generation of HIV protease inhibitors. The continued exploration of our hydroxylaminepentanamide (HAPA) transition-state isostere series of HIV protease inhibitors, which initially resulted in the identification of Crixivan (indinavir sulfate, MK-639, L-735,524), has now yielded MK-944a (L-756,423). This compound is potent, is selective, and competitively inhibits HIV-1 PR with a K(i) value of 0.049 nM. It stops the spread of the HIV(IIIb)-infected MT4 lymphoid cells at 25.0-50.0 nM, even in the presence of alpha(1) acid glycoprotein, human serum albumin, normal human serum, or fetal bovine serum. MK-944a has a longer half-life in several animal models (rats, dogs, and monkeys) than indinavir sulfate and is currently in advanced human clinical trials.


Subject(s)
Antiviral Agents/chemical synthesis , HIV Protease Inhibitors/chemical synthesis , HIV-1/drug effects , Indans/chemical synthesis , Piperazines/chemical synthesis , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Cattle , Cell Culture Techniques , Dogs , Drug Evaluation, Preclinical , Drug Resistance, Microbial , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/pharmacokinetics , HIV Protease Inhibitors/pharmacology , Haplorhini , Humans , Indans/chemistry , Indans/pharmacokinetics , Indans/pharmacology , Male , Piperazines/chemistry , Piperazines/pharmacokinetics , Piperazines/pharmacology , Protein Binding , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Urinary Calculi/chemically induced , Urinary Calculi/urine
16.
Drug Metab Dispos ; 28(4): 460-6, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10725315

ABSTRACT

L-754,394, a furanopyridine derivative, is an experimental HIV protease inhibitor. Previous studies from this laboratory have demonstrated that L-754,394 is cleared very rapidly in animals, and that this drug is a potent mechanism-based inactivator (suicide inhibitor) for CYP3A4 in human liver microsomes. Because L-754,394 is a high-clearance drug and an enzyme inactivator, it is expected that this drug will be subject to significant first-pass metabolism, and that the degree of enzyme inactivation will be dependent not only on the dose, but also on the route of administration. The purpose of this study is to examine the effects of dose and route of administration on the kinetics of L-754,394 using rats and dogs as animal models. In both rats and dogs, L-754,394 exhibited marked dose-dependent pharmacokinetics after i.v. and oral administration. Irrespective of i.v. or oral administration, the area under the plasma concentration-time curve from zero to infinity increased with dose in a greater than proportional manner. However, the magnitude of area under the plasma concentration-time curve from zero to infinity increase was much greater after oral dosing than after i.v. administration, indicating route-dependent pharmacokinetics. Data from in vitro and in vivo studies suggested that the dose- and route-dependent pharmacokinetics were due mainly to the inactivation (destruction) of the enzymes responsible for its own metabolism.


Subject(s)
Aryl Hydrocarbon Hydroxylases , HIV Protease Inhibitors/pharmacokinetics , Indans/pharmacokinetics , Piperazines/pharmacokinetics , Administration, Oral , Animals , Antibodies, Blocking/pharmacology , Area Under Curve , Chromatography, High Pressure Liquid , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Dogs , Dose-Response Relationship, Drug , HIV Protease Inhibitors/administration & dosage , HIV Protease Inhibitors/blood , In Vitro Techniques , Indans/administration & dosage , Indans/blood , Injections, Intravenous , Liver/enzymology , Liver/metabolism , Male , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Nonlinear Dynamics , Perfusion , Piperazines/administration & dosage , Piperazines/blood , Rats , Rats, Sprague-Dawley , Steroid Hydroxylases/antagonists & inhibitors , Steroid Hydroxylases/metabolism , Testosterone/blood
17.
Drug Metab Dispos ; 27(10): 1187-93, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10497146

ABSTRACT

Indinavir, a potent and specific inhibitor of HIV protease, is a known substrate of cytochrome P-450 (CYP) 3A and p-glycoprotein. The purpose of this study is to investigate and compare the inducing effect of dexamethasone (DEX) on CYP3A and p-glycoprotein in the hepatic and intestinal first-pass metabolism of indinavir in rats. Pretreatment of rats with DEX had little effect on the pharmacokinetics (Cl and T(1/2)) after i.v. administration of indinavir, whereas DEX markedly altered the peak concentration (C(max)) and bioavailability of indinavir after oral dosing. The C(max) decreased from 2.8 microM in control rats to 0.28 microM in DEX-treated rats, and bioavailability decreased from 28 to 12.4%. The decreased bioavailability after DEX pretreatment was due mainly to an increase in first-pass metabolism. Intestinal first-pass metabolism (E(G)) increased from 6% in control rats to 34% in DEX-treated rats, and hepatic first-pass metabolism (E(H)) increased from 65 to 82%. Analysis of in vitro kinetic data revealed that the increased intestinal and hepatic metabolism by DEX was attributed to an increase in the V(max), as a result of CYP3A induction, without a significant change in the K(m) values. DEX pretreatment also induced p-glycoprotein in the intestine and liver of rats. p-Glycoprotein appeared to increase the intestinal metabolism of indinavir whereas it had little effect on the hepatic metabolism of indinavir. Although it has been suggested that the role of intestinal metabolism for some drugs is quantitatively greater than that of hepatic metabolism in the overall first-pass metabolism, the contribution of intestinal metabolism to the overall first-pass metabolism of indinavir in rats is not quantitatively as important as the hepatic metabolism, regardless of DEX induction.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/biosynthesis , Anti-HIV Agents/pharmacokinetics , Aryl Hydrocarbon Hydroxylases , Cytochrome P-450 Enzyme System/biosynthesis , Dexamethasone/pharmacology , Indinavir/pharmacokinetics , Intestinal Mucosa/metabolism , Oxidoreductases, N-Demethylating/biosynthesis , Animals , Blotting, Western , Cytochrome P-450 CYP3A , Liver/metabolism , Male , Rats , Rats, Sprague-Dawley
18.
J Med Chem ; 41(23): 4466-74, 1998 Nov 05.
Article in English | MEDLINE | ID: mdl-9804686

ABSTRACT

We have addressed the key deficiency of noncovalent pyridinone acetamide thrombin inhibitor L-374,087 (1), namely, its modest half-lives in animals, by making a chemically stable 3-alkylaminopyrazinone bioisostere for its 3-sulfonylaminopyridinone core. Compound 3 (L-375,378), the closest aminopyrazinone analogue of 1, has comparable selectivity and slightly decreased efficacy but significantly improved pharmacokinetics in rats, dogs, and monkeys to 1. We have developed an efficient and versatile synthesis of 3, and this compound has been chosen for further preclinical and clinical development.


Subject(s)
Aminopyridines/chemical synthesis , Peptides/chemistry , Pyrazines/chemical synthesis , Pyridones/chemical synthesis , Thrombin/antagonists & inhibitors , Aminopyridines/chemistry , Aminopyridines/pharmacokinetics , Aminopyridines/pharmacology , Animals , Biological Availability , Crystallography, X-Ray , Dogs , Macaca mulatta , Models, Molecular , Molecular Mimicry , Pyrazines/chemistry , Pyrazines/pharmacokinetics , Pyrazines/pharmacology , Pyridones/chemistry , Pyridones/pharmacokinetics , Pyridones/pharmacology , Rats , Structure-Activity Relationship
19.
Biochem Pharmacol ; 56(2): 223-30, 1998 Jul 15.
Article in English | MEDLINE | ID: mdl-9698076

ABSTRACT

P450 complex formation and the unusual pharmacokinetics of methylenedioxyphenyl HIV protease inhibitors were examined by in vitro studies using human and rat liver microsomes and by in vivo oral dosing studies. In vitro spectral studies indicated that the formation of a P450 complex having absorbance maxima at 425 and 456 nm was time and concentration dependent; 27-60% of the total P450 was complexed in dexamethasone-induced rat liver microsomes after a 30-min incubation with 100 microM HIV protease inhibitors. Methoxy substitution on the phenyl ring of the methylenedioxyphenyl moiety increased formation of the P450 complex, whereas chlorine substitution markedly decreased the P450 complexation. Kinetic studies on the P450 complex formation indicated that both methoxy and chlorine substitution affected the maximum complex formation rate (Vmax), while it had little effect on Km values (approximately 10 microM). This complexation in human liver microsomes was inhibited markedly by an anti-CYP3A1 antibody. Furthermore, the P450 complex formation resulted in a time-dependent loss of CYP3A-catalyzed marker activities (testosterone 2beta/6beta-hydroxylase) in both rat and human liver microsomes. Collectively, these results point to the involvement of CYP3A isoforms in P450 complexation by methylenedioxyphenyl HIV protease inhibitors. Additionally, after oral administration to rats, one of these HIV protease inhibitors (Compound I), which complexed P450 to the greatest extent, showed no elimination over a period of 500 min after administration of the highest dose. It is suggested that formation of a quasi-irreversible metabolite-CYP3A complex with methylenedioxyphenyl HIV protease inhibitors was responsible for the CYP3A-selective time-dependent loss of catalytic function and the unusual dose-dependent pharmacokinetics after oral administration.


Subject(s)
Aryl Hydrocarbon Hydroxylases , Cytochrome P-450 Enzyme System/metabolism , HIV Protease Inhibitors/pharmacology , Isoenzymes/metabolism , Microsomes, Liver/drug effects , Animals , Biotransformation , Catalysis , Chromatography, High Pressure Liquid , Cytochrome P-450 CYP3A , HIV Protease Inhibitors/metabolism , HIV Protease Inhibitors/pharmacokinetics , Half-Life , Humans , Hydroxylation , Male , Microsomes, Liver/enzymology , Microsomes, Liver/metabolism , Rats , Rats, Sprague-Dawley
20.
J Med Chem ; 41(17): 3210-9, 1998 Aug 13.
Article in English | MEDLINE | ID: mdl-9703466

ABSTRACT

As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site.


Subject(s)
Cyclohexylamines/chemical synthesis , Dipeptides/chemical synthesis , Fibrinolytic Agents/chemical synthesis , Thrombin/antagonists & inhibitors , Administration, Oral , Animals , Binding Sites , Biological Availability , Computer Simulation , Crystallography, X-Ray , Cyclohexylamines/chemistry , Cyclohexylamines/pharmacokinetics , Dipeptides/chemistry , Dipeptides/pharmacokinetics , Dogs , Drug Design , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacokinetics , Fibrinolytic Agents/pharmacology , Hydrogen Bonding , Macaca fascicularis , Models, Molecular , Molecular Conformation , Molecular Structure , Rats , Resins, Plant , Structure-Activity Relationship , Thrombin/chemistry
SELECTION OF CITATIONS
SEARCH DETAIL
...