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1.
Bioorg Med Chem Lett ; 23(23): 6459-62, 2013 Dec 01.
Article in English | MEDLINE | ID: mdl-24119554

ABSTRACT

The synthesis and structure-activity relationship of decahydroisoquinoline derivatives with various benzoic acid substitutions as GluK1 antagonists are described. Potent and selective antagonists were selected for a tailored prodrug approach in order to facilitate the evaluation of the new compounds in pain models after oral administration. Several diester prodrugs allowed for acceptable amino acid exposure and moderate efficacy in vivo.


Subject(s)
Isoquinolines/pharmacology , Pain/drug therapy , Prodrugs/pharmacology , Receptors, Kainic Acid/antagonists & inhibitors , Administration, Oral , Amino Acid Sequence , Animals , Disease Models, Animal , Haplorhini , Isoquinolines/chemistry , Molecular Sequence Data , Prodrugs/chemistry , Receptors, Kainic Acid/chemistry , Structure-Activity Relationship
2.
Bioorg Med Chem Lett ; 23(23): 6463-6, 2013 Dec 01.
Article in English | MEDLINE | ID: mdl-24140446

ABSTRACT

We have explored the decahydroisoquinoline scaffold, bearing a phenyl tetrazole, as GluK1 antagonists with potential as oral analgesics. We have established the optimal linker atom between decahydroisoquinoline and phenyl rings and demonstrated an improvement of both the affinity for the GluK1 receptor and the selectivity against the related GluA2 receptor with proper phenyl substitution. In this Letter, we also disclose in vivo data that led to the discovery of LY545694·HCl, a compound with oral efficacy in two persistent pain models.


Subject(s)
Isoquinolines/pharmacology , Pain/drug therapy , Prodrugs/pharmacology , Receptors, Kainic Acid/antagonists & inhibitors , Tetrazoles/pharmacology , Administration, Oral , Amino Acid Sequence , Animals , Disease Models, Animal , Isoquinolines/chemistry , Male , Molecular Sequence Data , Prodrugs/chemistry , Rats , Rats, Sprague-Dawley , Receptors, Kainic Acid/chemistry , Structure-Activity Relationship , Tetrazoles/chemistry
3.
Drug Metab Dispos ; 39(5): 740-9, 2011 May.
Article in English | MEDLINE | ID: mdl-21346003

ABSTRACT

2-Methylalanyl-N-{1-[(1R)-1-(4-fluorophenyl)-1-methyl-2-oxo-2-pyrrolidin-1-ylethyl]-1H-imidazol-4-yl}-5-phenyl-D-norvalinamide (LY654322) was rapidly cleared in rats and dogs by renal excretion of parent and metabolism (oxidative and hydrolytic). Among the metabolites identified in the urine of rats and dogs was M25, which was structurally unusual. Indeed, the characterization of M25 and investigation into its disposition relied on the convergence of diverse analytical methodologies. M25 eluted after the parent on reverse-phase chromatography with an MH(+) at m/z 598 (parent + 35 Da). Given its increased lipophilicity and its mass difference compared with the parent, it was evident that M25 was not a phase 2 conjugate. Subsequent liquid chromatography with multiple-stage tandem mass spectrometry and accurate mass experiments identified the structure of M25 as having two replicates of the 1-(4-fluorophenyl)-1-methyl-2-oxo-2-pyrrolidinyl substructure flanking a central aromatic core of composition C(7)H(3)N(5) that was refractory to fragmentation. Compared with the UV spectrum of the parent (λ(max) = 213 nm), M25 displayed a bathochromic shift (λ(max) = 311 nm), which substantiated extensive conjugation within the central core. Subsequent NMR analysis of M25 isolated from dog urine coupled with molecular modeling revealed the structure to be consistent with a diimidazopyridine core with two symmetrically substituted 1-(4-fluorophenyl)-1-methyl-2-oxo-2-pyrrolidinyl moieties. Using a structural analog with a chromophore similar to M25, LC-UV was used to quantitate M25 and determine its urinary disposition. The formation of M25 appears consistent with hydrolysis of LY654322 to an aminoimidazole, dimerization of the latter with the loss of NH(3), C-formylation, and subsequent ring closure and aromatization with loss of H(2)O.


Subject(s)
Dipeptides/chemistry , Dipeptides/metabolism , Heterocyclic Compounds, 3-Ring/analysis , Heterocyclic Compounds, 3-Ring/chemistry , Imidazoles/chemistry , Imidazoles/metabolism , Pyridines/analysis , Pyridines/chemistry , Receptors, Ghrelin/agonists , Animals , Dipeptides/blood , Dipeptides/pharmacokinetics , Dipeptides/pharmacology , Dogs , Female , Human Growth Hormone/metabolism , Imidazoles/blood , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Male , Rats , Rats, Inbred F344 , Receptors, Ghrelin/metabolism
4.
J Pharmacol Exp Ther ; 318(2): 772-81, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16690725

ABSTRACT

The excitatory neurotransmitter glutamate has been implicated in both migraine and persistent pain. The identification of the kainate receptor GLU(K5) in dorsal root ganglia, the dorsal horn, and trigeminal ganglia makes it a target of interest for these indications. We examined the in vitro and in vivo pharmacology of the competitive GLU(K5)-selective kainate receptor antagonist LY466195 [(3S,4aR,6S,8aR)-6-[[(2S)-2-carboxy-4,4-difluoro-1-pyrrolidinyl]-methyl]decahydro-3-isoquinolinecarboxylic acid)], the most potent GLU(K5) antagonist described to date. Comparisons were made to the competitive GLU(K5)/alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist LY293558 [(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]-decahydroisoquinoline-3-carboxylic acid], other decahydroisoquinoline GLU(K5) receptor antagonists, and the noncompetitive AMPA receptor antagonist LY300168 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodi-azepine]. When characterized electrophysiologically in rat dorsal root ganglion neurons, LY466195 antagonized kainate (30 microM)-induced currents with an IC50 value of 0.045 +/- 0.011 microM. In HEK293 cells transfected with GLU(K5), GLU(K2)/GLU(K5), or GLU(K5)/GLU(K6) receptors, LY466195 produced IC50 values of 0.08 +/- 0.02, 0.34 +/- 0.17, and 0.07 +/- 0.02 microM, respectively. LY466195 was efficacious in a dural plasma protein extravasation (PPE) model of migraine with an ID100 value of 100 microg/kg i.v. LY466195 was also efficacious in the c-fos migraine model, with a dose of 1 microg/kg i.v. significantly reducing the number of Fos-positive cells in the rat nucleus caudalis after electrical stimulation of the trigeminal ganglion. Furthermore, LY466195 showed no contractile activity in the rabbit saphenous vein in vitro. The diethyl ester prodrug of LY466195 was also efficacious in the same PPE and c-fos models after oral administration at doses of 10 and 100 microg/kg, respectively while having no N-methyl-D-aspartate antagonist-like behavioral effects at oral doses up to 100 mg/kg.


Subject(s)
Isoquinolines/pharmacology , Receptors, Kainic Acid/antagonists & inhibitors , Animals , Benzodiazepines/pharmacology , Binding, Competitive/drug effects , Blood Proteins/metabolism , Calcium/metabolism , Electrophysiology , Excitatory Amino Acid Antagonists/pharmacology , Humans , In Vitro Techniques , Ligands , Male , Migraine Disorders/metabolism , Motor Activity/drug effects , Muscle Contraction/drug effects , Muscle, Smooth, Vascular/drug effects , Neurons/drug effects , Neurons/metabolism , Phencyclidine/pharmacology , Proto-Oncogene Proteins c-fos/biosynthesis , Rabbits , Rats , Receptors, AMPA/antagonists & inhibitors , Saphenous Vein/cytology , Saphenous Vein/drug effects , Transfection
5.
J Med Chem ; 48(13): 4200-3, 2005 Jun 30.
Article in English | MEDLINE | ID: mdl-15974569

ABSTRACT

Amino acids 5 and 7, two potent and selective competitive GluR5 KA receptor antagonists, exhibited high GluR5 receptor affinity over other glutamate receptors. Their ester prodrugs 6 and 8 were orally active in three models of pain: reversal of formalin-induced paw licking, carrageenan-induced thermal hyperalgesia, and capsaicin-induced mechanical hyperalgesia.


Subject(s)
Amino Acids/pharmacology , Analgesics/chemistry , Analgesics/pharmacology , Pain/drug therapy , Receptors, Kainic Acid/antagonists & inhibitors , Analgesics/pharmacokinetics , Animals , Biological Availability , Cell Line , Disease Models, Animal , Humans , Hyperalgesia/drug therapy , Rats , Receptors, AMPA/metabolism , Recombinant Proteins/metabolism , Spinal Cord/physiopathology , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism
6.
Drug Metab Dispos ; 32(9): 966-72, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15319338

ABSTRACT

Phase I oxidative metabolism of nitrogen-containing drug molecules to their corresponding N-oxides is a common occurrence. There are instances where liquid chromatography/tandem mass spectometry techniques are inadequate to distinguish this pathway from other oxidation processes, including C-hydroxylations and other heteroatom oxidations, such as sulfur to sulfoxide. Therefore, the purpose of the present study was to develop and optimize an efficient and practical chemical method to selectively convert N-oxides to their corresponding amines suitable for drug metabolism applications. Our results indicated that efficient conversion of N-oxides to amines could be achieved with TiCl(3) and poly(methylhydrosiloxane). Among them, we found TiCl(3) to be a facile and easy-to-use reagent, specifically applicable to drug metabolism. There are a few reports describing the use of TiCl(3) to reduce N-O bonds in drug metabolism studies, but this methodology has not been widely used. Our results indicated that TiCl(3) is nearly as efficient when the reductions were carried out in the presence of biological matrices, including plasma and urine. Finally, we have shown a number of examples where TiCl(3) can be successfully used to selectively reduce N-oxides in the presence of sulfoxides and other labile groups.


Subject(s)
Amines/metabolism , Cyclic N-Oxides/metabolism , Pharmaceutical Preparations/metabolism , Animals , Catalysis , Chromatography, Liquid , Dogs , Drug Evaluation, Preclinical/methods , Female , Furans/chemistry , Furans/metabolism , Hydroxylation/drug effects , Isomerism , Isoquinolines/chemistry , Isoquinolines/metabolism , Mass Spectrometry , Molecular Structure , Oxidation-Reduction/drug effects , Palladium/chemistry , Pyridazines/metabolism , Rats , Serum Albumin/chemistry , Serum Albumin/metabolism , Siloxanes/metabolism , Sulfoxides/metabolism , Temperature , Time Factors , Titanium/metabolism , Vinca Alkaloids/blood , Vinca Alkaloids/urine , Water
7.
Drug Metab Dispos ; 31(1): 88-97, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12485957

ABSTRACT

These studies were designed to characterize the disposition and metabolism of atomoxetine hydrochloride [(-)-N-methyl-gamma-(2-methylphenoxy)benzenepropanamine hydrochloride; formerly know as tomoxetine hydrochloride] in Fischer 344 rats and beagle dogs. Atomoxetine was well absorbed from the gastrointestinal tract and cleared primarily by metabolism with the majority of its metabolites being excreted into the urine, 66% of the total dose in the rat and 48% in the dog. Fecal excretion, 32% of the total dose in the rat and 42% in the dog, appears to be due to biliary elimination and not due to unabsorbed dose. Nearly the entire dose was excreted within 24 h in both species. In the rat, low oral bioavailability was observed (F = 4%) compared with the high oral bioavailability in dog (F = 74%). These differences appear to be almost purely mediated by the efficient first-pass hepatic clearance of atomoxetine in rat. The biotransformation of atomoxetine was similar in the rat and dog, undergoing aromatic ring hydroxylation, benzylic oxidation (rat only), and N-demethylation. The primary oxidative metabolite of atomoxetine was 4-hydroxyatomoxetine, which was subsequently conjugated forming O-glucuronide and O-sulfate (dog only) metabolites. Although subtle differences were observed in the excretion and biotransformation of atomoxetine in rats and dogs, the primary difference observed between these species was the extent of first-pass metabolism and the degree of systemic exposure to atomoxetine and its metabolites.


Subject(s)
Propylamines/pharmacokinetics , Propylamines/urine , Administration, Oral , Animals , Atomoxetine Hydrochloride , Biological Availability , Dogs , Female , Male , Microsomes, Liver/metabolism , Propylamines/chemistry , Propylamines/metabolism , Rats , Rats, Inbred F344 , Species Specificity
8.
Drug Metab Dispos ; 31(1): 98-107, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12485958

ABSTRACT

The role of the polymorphic cytochrome p450 2D6 (CYP2D6) in the pharmacokinetics of atomoxetine hydrochloride [(-)-N-methyl-gamma-(2-methylphenoxy)benzenepropanamine hydrochloride; LY139603] has been documented following both single and multiple doses of the drug. In this study, the influence of the CYP2D6 polymorphism on the overall disposition and metabolism of a 20-mg dose of (14)C-atomoxetine was evaluated in CYP2D6 extensive metabolizer (EM; n = 4) and poor metabolizer (PM; n = 3) subjects under steady-state conditions. Atomoxetine was well absorbed from the gastrointestinal tract and cleared primarily by metabolism with the preponderance of radioactivity being excreted into the urine. In EM subjects, the majority of the radioactive dose was excreted within 24 h, whereas in PM subjects the majority of the dose was excreted by 72 h. The biotransformation of atomoxetine was similar in all subjects undergoing aromatic ring hydroxylation, benzylic oxidation, and N-demethylation with no CYP2D6 phenotype-specific metabolites. The primary oxidative metabolite of atomoxetine was 4-hydroxyatomoxetine, which was subsequently conjugated forming 4-hydroxyatomoxetine-O-glucuronide. Due to the absence of CYP2D6 activity, the systemic exposure to radioactivity was prolonged in PM subjects (t(1/2) = 62 h) compared with EM subjects (t(1/2) = 18 h). In EM subjects, atomoxetine (t(1/2) = 5 h) and 4-hydroxyatomoxetine-O-glucuronide (t(1/2) = 7 h) were the principle circulating species, whereas atomoxetine (t(1/2) = 20 h) and N-desmethylatomoxetine (t(1/2) = 33 h) were the principle circulating species in PM subjects. Although differences were observed in the excretion and relative amounts of metabolites formed, the primary difference observed between EM and PM subjects was the rate at which atomoxetine was biotransformed to 4-hydroxyatomoxetine.


Subject(s)
Cytochrome P-450 CYP2D6/genetics , Cytochrome P-450 CYP2D6/metabolism , Propylamines/metabolism , Adult , Atomoxetine Hydrochloride , Biotransformation/physiology , Humans , Male , Middle Aged , Propylamines/blood , Propylamines/chemistry , Propylamines/urine
9.
J Med Chem ; 45(20): 4383-6, 2002 Sep 26.
Article in English | MEDLINE | ID: mdl-12238915

ABSTRACT

Amino diacid 3, a highly selective competitive GluR5 kainate receptor antagonist, exhibited high GluR5 receptor affinity and selectivity over other glutamate receptors. Its diethyl ester prodrug 4 was orally active in two models of migraine: the neurogenic dural plasma protein extravasation model and the nucleus caudalis c-fos expression model. These data suggest that a GluR5 kainate receptor antagonist might be an efficacious antimigraine therapy with a novel mechanism of action.


Subject(s)
Carboxylic Acids/chemical synthesis , Esters/chemical synthesis , Excitatory Amino Acid Antagonists/chemical synthesis , Isoquinolines/chemical synthesis , Migraine Disorders/drug therapy , Prodrugs/chemical synthesis , Receptors, Kainic Acid/antagonists & inhibitors , Acute Disease , Administration, Oral , Animals , Biological Availability , Calcium/metabolism , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Cell Line , Disease Models, Animal , Dose-Response Relationship, Drug , Esters/chemistry , Esters/pharmacology , Excitatory Amino Acid Antagonists/chemistry , Excitatory Amino Acid Antagonists/pharmacology , Humans , Isoquinolines/chemistry , Isoquinolines/pharmacology , Prodrugs/chemistry , Prodrugs/pharmacology , Radioligand Assay , Rats , Rats, Wistar
10.
J Pharmacol Toxicol Methods ; 47(3): 161-8, 2002.
Article in English | MEDLINE | ID: mdl-12628307

ABSTRACT

INTRODUCTION: Glucuronidation by the uridine diphosphate glucuronosyltransferases (UGTs) plays a pivotal role in the clearance mechanism of both xenobiotics and endobiotics. The detection of glucuronides at low micromolar concentrations is required to accurately model in vitro enzyme kinetics and in vivo pharmacokinetics. However, relatively few glucuronides are currently available as standards for developing liquid chromatography and mass spectroscopy (LC/MS) bioanalytical methods. METHODS: The glucuronidation capacity of hepatic microsomes prepared from rat (RLM), dog (DLM), monkey (MLM), and human (HLM) was examined for five xenobiotic substrates. In each case, glucuronide standards were produced using the enzyme source most efficient for the production of that specific glucuronide. RESULTS: Dog hepatic microsomes were used to produce glucuronides for anthraflavic acid (yield: 14 mg), buprenorphine (yield: 14 mg), and octylgallate (total yield: 13 mg), whereas propofol glucuronide (yield: 20 mg), and ethinylestradiol glucuronide (yield: 8 mg) were prepared using HLM. All glucuronides were characterized by LC/MS/MS and nuclear magnetic resonance (NMR) spectroscopy. DISCUSSION: The multimilligram quantities of glucuronide standards produced by this method have many applications throughout drug discovery and toxicology. In addition to allowing the quantification of glucuronide formation from in vitro and in vivo studies, the authentic standards produced could also be used to assess potential pharmacological or toxicological effects of metabolites.


Subject(s)
Gallic Acid/analogs & derivatives , Glucuronides/biosynthesis , Microsomes, Liver/metabolism , Reference Standards , Xenobiotics/metabolism , Animals , Anthraquinones/metabolism , Buprenorphine/metabolism , Chromatography, High Pressure Liquid , Dogs , Ethinyl Estradiol/metabolism , Gallic Acid/metabolism , Glucuronides/analysis , Glucuronosyltransferase/metabolism , Haplorhini , Humans , Magnetic Resonance Spectroscopy , Propofol/metabolism , Rats
11.
Drug Metab Dispos ; 30(1): 27-33, 2002 Jan.
Article in English | MEDLINE | ID: mdl-11744608

ABSTRACT

Compound LY354740 [(+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid], an analog of glutamic acid, is a selective group 2 metabotropic glutamate receptor agonist in clinical development for the treatment of anxiety. Studies have been conducted to characterize the absorption, disposition, metabolism, and excretion of LY354740 in rats and dogs after intravenous bolus or oral administration. Plasma concentrations of LY354740 were measured using a validated gas chromatography/mass spectrometry assay. In rats, LY354740 demonstrated linear pharmacokinetics after oral administration from 30 to 1000 mg/kg. The oral bioavailability of LY354740 was approximately 10% in rats and 45% in dogs. In the dog, food decreased the mean area under the plasma concentration-time curve value by approximately 34%, hence, decreasing the oral bioavailability of the compound. Excretion studies in both rats and dogs indicate that the absorbed drug is primarily eliminated via renal excretion. In addition, tissue distribution in rats showed that the highest levels of radioactivity were in the kidney and gastrointestinal tract, which is consistent with the excretion studies. Metabolism of LY354740 was evaluated in vitro using rat and dog liver microsomes and rat liver slices. In addition, urine and fecal samples from rat and dog excretion studies were profiled using HPLC with radio-detection. These evaluations indicated that neither rats nor dogs metabolized LY354740. In summary, LY354740 is poorly absorbed in rats, moderately absorbed in dogs, and rapidly excreted as unchanged drug in the urine.


Subject(s)
Anti-Anxiety Agents/pharmacokinetics , Bridged Bicyclo Compounds/pharmacokinetics , Excitatory Amino Acid Agonists/pharmacokinetics , Receptors, Metabotropic Glutamate/agonists , Administration, Oral , Animals , Anti-Anxiety Agents/metabolism , Biological Availability , Blood Proteins/metabolism , Bridged Bicyclo Compounds/metabolism , Dogs , Drug Evaluation, Preclinical , Erythrocytes/metabolism , Excitatory Amino Acid Agonists/metabolism , Female , Humans , In Vitro Techniques , Male , Protein Binding , Rats , Rats, Inbred F344 , Receptors, Metabotropic Glutamate/metabolism , Tissue Distribution
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