ABSTRACT
ABT-072 is a non-nucleoside HCV NS5B polymerase inhibitor that was discovered as part of a program to identify new direct-acting antivirals (DAAs) for the treatment of HCV infection. This compound was identified during a medicinal chemistry effort to improve on an original lead, inhibitor 1, which we described in a previous publication. Replacement of the amide linkage in 1 with a trans-olefin resulted in improved compound permeability and solubility and provided much better pharmacokinetic properties in preclinical species. Replacement of the dihydrouracil in 1 with an N-linked uracil provided better potency in the genotype 1 replicon assay. Results from phase 1 clinical studies supported once-daily oral dosing with ABT-072 in HCV infected patients. A phase 2 clinical study that combined ABT-072 with the HCV protease inhibitor ABT-450 provided a sustained virologic response at 24 weeks after dosing (SVR24) in 10 of 11 patients who received treatment.
Subject(s)
Cytosine/analogs & derivatives , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Hepacivirus/enzymology , Stilbenes/chemistry , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Biological Availability , Chemistry Techniques, Synthetic , Cytosine/chemical synthesis , Cytosine/chemistry , Cytosine/pharmacokinetics , Cytosine/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Humans , Permeability , Stereoisomerism , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , Tissue Distribution , Viral Nonstructural Proteins/chemistryABSTRACT
Research toward a next-generation HCV NS5A inhibitor has identified fluorobenzimidazole analogs that demonstrate potent, broad-genotype in vitro activity against HCV genotypes 1-6 replicons as well as HCV NS5A variants that are orders of magnitude less susceptible to inhibition by first-generation NS5A inhibitors in comparison to wild-type replicons. The fluorobenzimidazole inhibitors have improved pharmacokinetic properties in comparison to non-fluorinated benzimidazole analogs. Discovery of these inhibitors was facilitated by exploring SAR in a structurally simplified inhibitor series.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Hepacivirus/drug effects , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/pharmacokinetics , Benzimidazoles/pharmacokinetics , Dogs , Genotype , Halogenation , Hepacivirus/genetics , Hepacivirus/metabolism , Hepatitis C/drug therapy , Humans , Mice , Rats , Replicon/drug effects , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolismABSTRACT
Leucine is an essential branched-chain amino acid that acts as a substrate for protein synthesis and as a signaling molecule. Leucine not incorporated into muscle protein is ultimately oxidized through intermediates such as ß-hydroxy-ß-methylbutyrate (HMB) which itself is reported to enhance muscle mass and function in rats and humans. HMB has been reported in the plasma following oral leucine administration in sheep and pigs but not in Sprague-Dawley rats, the standard preclinical model. Therefore, we conducted radiolabeled absorption, distribution, metabolism and excretion (ADME) studies in rats using a low (3 mg/kg) or high dose (1,000 mg/kg) of (14)C-leucine. Blood, tissue, and urine samples were analyzed for (14)C-leucine and its metabolites by HPLC-MS. Our results show for the first time that (14)C-HMB appears in plasma and urine of rats following an oral dose of (14)C-leucine. (14)C-leucine appears in plasma as (14)C-α-ketoisocaproic acid (KIC) with a slower time course than (14)C-HMB, a putative product of KIC. Further, two novel metabolites of leucine were detected in urine, N-acetyl leucine and glycyl leucine. Mass balance studies demonstrate that excretory routes accounted for no more than 0.9 % of the radiolabel and approximately 61 % of the dose was recovered in the carcass. Approximately 65 % of the dose was recovered in total, suggesting that approximately one-third of the leucine dose is oxidized to CO2. In conclusion, this study demonstrates endogenous production of HMB from leucine in adult rats, a standard preclinical model used to guide design of clinical trials in nutrition.
Subject(s)
Dipeptides/urine , Keto Acids/blood , Leucine/analogs & derivatives , Leucine/pharmacokinetics , Valerates/blood , Animals , Biological Transport , Carbon Radioisotopes , Chromatography, High Pressure Liquid , Dipeptides/blood , Intestinal Absorption/physiology , Keto Acids/urine , Leucine/blood , Leucine/urine , Male , Mass Spectrometry , Oxidation-Reduction , Rats , Rats, Sprague-Dawley , Valerates/urineABSTRACT
We describe here N-phenylpyrrolidine-based inhibitors of HCV NS5A with excellent potency, metabolic stability, and pharmacokinetics. Compounds with 2S,5S stereochemistry at the pyrrolidine ring provided improved genotype 1 (GT1) potency compared to the 2R,5R analogues. Furthermore, the attachment of substituents at the 4-position of the central N-phenyl group resulted in compounds with improved potency. Substitution with tert-butyl, as in compound 38 (ABT-267), provided compounds with low-picomolar EC50 values and superior pharmacokinetics. It was discovered that compound 38 was a pan-genotypic HCV inhibitor, with an EC50 range of 1.7-19.3 pM against GT1a, -1b, -2a, -2b, -3a, -4a, and -5a and 366 pM against GT6a. Compound 38 decreased HCV RNA up to 3.10 log10 IU/mL during 3-day monotherapy in treatment-naive HCV GT1-infected subjects and is currently in phase 3 clinical trials in combination with an NS3 protease inhibitor with ritonavir (r) (ABT-450/r) and an NS5B non-nucleoside polymerase inhibitor (ABT-333), with and without ribavirin.
Subject(s)
Anilides/pharmacology , Antiviral Agents/pharmacology , Carbamates/pharmacology , Genotype , Hepacivirus/drug effects , Sulfonamides/pharmacology , Uracil/analogs & derivatives , Viral Nonstructural Proteins/antagonists & inhibitors , 2-Naphthylamine , Anilides/chemistry , Anilides/pharmacokinetics , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Biological Availability , Carbamates/chemistry , Carbamates/pharmacokinetics , Cell Line , Drug Discovery , Hepacivirus/enzymology , Humans , Proline , Rats , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , Uracil/chemistry , Uracil/pharmacokinetics , Uracil/pharmacology , ValineABSTRACT
The synthesis and structure-activity relationships of a novel aryl uracil series which contains a fused 5,6-bicyclic ring unit for HCV NS5B inhibition is described. Several analogs display replicon cell culture potencies in the low nanomolar range along with excellent rat pharmacokinetic values.
Subject(s)
Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Uracil/antagonists & inhibitors , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/pharmacokinetics , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Hepacivirus/enzymology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , RNA-Dependent RNA Polymerase/metabolism , Rats , Structure-Activity Relationship , Uracil/pharmacology , Viral Nonstructural Proteins/metabolismABSTRACT
A high-throughput screen against human DGAT-1 led to the identification of a core structure that was subsequently optimized to afford the potent, selective, and orally bioavailable compound 14. Oral administration at doses ≥0.03 mg/kg significantly reduced postprandial triglycerides in mice following an oral lipid challenge. Further assessment in both acute and chronic safety pharmacology and toxicology studies demonstrated a clean profile up to high plasma levels, thus culminating in the nomination of 14 as clinical candidate ABT-046.
Subject(s)
Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Administration, Oral , Animals , Biological Availability , Caco-2 Cells , Databases, Factual , Diacylglycerol O-Acyltransferase/chemistry , Dogs , Female , Ferrets , Gastrointestinal Transit/drug effects , HeLa Cells , Hemodynamics/drug effects , Humans , Hyperlipidemias/blood , Hyperlipidemias/drug therapy , Male , Mice , Mice, Inbred C57BL , Microsomes, Liver/metabolism , Postprandial Period , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/chemistry , Structure-Activity Relationship , Triglycerides/blood , Vomiting/chemically inducedABSTRACT
A series of quinoline derivatives was synthesized as potential bioisosteric replacements for the benzothiadiazine moiety of earlier Hepatitis C NS5B polymerase inhibitors. Several of these compounds exhibited potent activity in enzymatic and replicon assays.
Subject(s)
Benzothiadiazines/pharmacology , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Benzothiadiazines/chemistry , Hepacivirus/enzymology , Hepacivirus/physiology , Protease Inhibitors/chemistry , Virus ReplicationABSTRACT
Benzothiadiazine inhibitors of the HCV NS5B RNA-dependent RNA polymerase are an important class of non-nucleoside inhibitors that have received considerable attention in the search for novel HCV therapeutics. Research in our laboratories has identified a novel series of tetracyclic benzothiadiazine inhibitors of HCV polymerase bearing a benzylamino substituent on the B-ring. Compounds in this series exhibit low-nanomolar activities in both genotypes 1a and 1b polymerase inhibition assays and subgenomic replicon assays. Optimization of pharmacokinetic properties in rat led to compound 30, which has good oral bioavailability (F = 56%) and a favorable tissue distribution drug profile, with high liver to plasma ratios. Compound 30 is a potent inhibitor in replicon assays, with EC(50) values of 10 and 6 nM against genotypes 1a and 1b, respectively.
Subject(s)
Benzothiadiazines/chemical synthesis , Benzothiadiazines/pharmacology , Hepacivirus/enzymology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Benzothiadiazines/pharmacokinetics , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Genotype , Hepacivirus/genetics , Liver/metabolism , Microbial Sensitivity Tests , Rats , Structure-Activity Relationship , Tissue DistributionABSTRACT
The hepatitis C virus (HCV) NS5B polymerase is essential for viral replication and has been a prime target for drug discovery research. Our efforts directed toward the discovery of HCV polymerase inhibitors resulted in the identification of unsymmetrical dialkyl-hydroxynaphthalenoyl-benzothiadiazines 2 and 3. The most active compound displayed activity in genotypes 1a and 1b polymerase and replicon cell culture inhibition assays at subnanomolar and low nanomolar concentrations, respectively. It also displayed an excellent pharmacokinetic profile in rats, with a plasma elimination half-life after intravenous dosing of 4.5 h, oral bioavailability of 77%, and a peak liver concentration of 21.8 microg/mL.
Subject(s)
Benzothiadiazines/chemical synthesis , Benzothiadiazines/pharmacology , DNA-Directed RNA Polymerases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Hepacivirus/enzymology , Animals , Benzothiadiazines/pharmacokinetics , Biological Availability , Enzyme Inhibitors/pharmacokinetics , Half-Life , Humans , Magnetic Resonance Spectroscopy , Rats , Spectrometry, Mass, Electrospray IonizationABSTRACT
4,4-Dialkyl-1-hydroxy-3-oxo-3.4-dihydronaphthalene-3-yl benzothiadiazine derivatives were synthesized and evaluated as inhibitors of genotypes 1a and 1b HCV NS5B polymerase. A number of these compounds exhibited potent activity against genotypes 1a and 1b HCV polymerase in both enzymatic and cell culture activities. A representative compound also showed favorable pharmacokinetics in the rat.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Animals , Area Under Curve , Chemistry, Pharmaceutical/methods , Drug Design , Genotype , Infusions, Intravenous , Inhibitory Concentration 50 , Models, Chemical , Rats , Viral Nonstructural Proteins/geneticsABSTRACT
A highly potent and selective DGAT-1 inhibitor was identified and used in rodent models of obesity and postprandial chylomicron excursion to validate DGAT-1 inhibition as a novel approach for the treatment of metabolic diseases. Specifically, compound 4a conferred weight loss and a reduction in liver triglycerides when dosed chronically in DIO mice and depleted serum triglycerides following a lipid challenge in a dose-dependent manner, thus, reproducing major phenotypical characteristics of DGAT-1(-/-) mice.
Subject(s)
Anti-Obesity Agents/chemical synthesis , Cycloheptanes/chemical synthesis , Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Hypolipidemic Agents/chemical synthesis , Keto Acids/chemical synthesis , Urea/analogs & derivatives , Urea/chemical synthesis , Animals , Anti-Obesity Agents/pharmacokinetics , Anti-Obesity Agents/pharmacology , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/pharmacokinetics , Biphenyl Compounds/pharmacology , Cycloheptanes/pharmacokinetics , Cycloheptanes/pharmacology , Diacylglycerol O-Acyltransferase/genetics , Eating/drug effects , Humans , Hypolipidemic Agents/pharmacokinetics , Hypolipidemic Agents/pharmacology , Isoenzymes/antagonists & inhibitors , Isoenzymes/genetics , Keto Acids/pharmacokinetics , Keto Acids/pharmacology , Liver/metabolism , Mice , Mice, Mutant Strains , Stereoisomerism , Structure-Activity Relationship , Triglycerides/metabolism , Urea/pharmacokinetics , Urea/pharmacology , Weight LossABSTRACT
A-837093 is a potent and specific nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase. It possesses nanomolar potencies in both enzymatic and replicon-based cell culture assays. In rats and dogs this compound demonstrated an oral plasma half-life of greater than 7 h, and its bioavailability was >60%. In monkeys it had a half-life of 1.9 h and 15% bioavailability. Its antiviral efficacy was evaluated in two chimpanzees infected with HCV in a proof-of-concept study. The design included oral dosing of 30 mg per kg of body weight twice a day for 14 days, followed by a 14-day posttreatment observation. Maximum viral load reductions of 1.4 and 2.5 log(10) copies RNA/ml for genotype 1a- and 1b-infected chimpanzees, respectively, were observed within 2 days after the initiation of treatment. After this initial drop in the viral load, a rebound of plasma HCV RNA was observed in the genotype 1b-infected chimpanzee, while the genotype 1a-infected chimpanzee experienced a partial rebound that lasted throughout the treatment period. Clonal analysis of NS5B gene sequences derived from the plasma of A-837093-treated chimpanzees revealed the presence of several mutations associated with resistance to A-837093, including Y448H, G554D, and D559G in the genotype 1a-infected chimpanzee and C316Y and G554D in the genotype 1b-infected chimpanzee. The identification of resistance-associated mutations in both chimpanzees is consistent with the findings of in vitro selection studies, in which many of the same mutations were selected. These findings validate the antiviral efficacy and resistance development of benzothiadiazine HCV polymerase inhibitors in vivo.
Subject(s)
Antiviral Agents/pharmacokinetics , Benzothiadiazines/pharmacokinetics , Cyclic S-Oxides/pharmacokinetics , Enzyme Inhibitors/pharmacokinetics , Hepacivirus/enzymology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Animals , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Benzothiadiazines/chemistry , Benzothiadiazines/therapeutic use , Biological Availability , Cyclic S-Oxides/chemistry , Cyclic S-Oxides/therapeutic use , Disease Models, Animal , Dogs , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Genotype , Haplorhini , Hepacivirus/drug effects , Hepacivirus/genetics , Hepatitis C/blood , Hepatitis C/drug therapy , Hepatitis C/virology , Humans , Molecular Structure , Pan troglodytes , Phenotype , RNA, Viral/blood , RNA-Dependent RNA Polymerase/genetics , Rats , Viral Load , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/geneticsABSTRACT
Stearoyl-CoA desaturase 1 (SCD1) catalyzes the committed step in the biosynthesis of monounsaturated fatty acids from saturated, long-chain fatty acids. Studies with SCD1 knockout mice have established that these animals are lean and protected from leptin deficiency-induced and diet-induced obesity, with greater whole body insulin sensitivity than wild-type animals. In this work, we have discovered a series of potent, selective, orally bioavailable SCD1 inhibitors based on a known pyridazine carboxamide template. The representative lead inhibitor 28c also demonstrates excellent cellular activity in blocking the conversion of saturated long-chain fatty acid-CoAs (LCFA-CoAs) to monounsaturated LCFA-CoAs in HepG2 cells.
Subject(s)
Oxadiazoles/chemical synthesis , Pyridazines/chemical synthesis , Stearoyl-CoA Desaturase/antagonists & inhibitors , Acyl Coenzyme A/metabolism , Animals , Biological Availability , Cell Line, Tumor , Humans , In Vitro Techniques , Mice , Microsomes, Liver/metabolism , Oxadiazoles/pharmacokinetics , Oxadiazoles/pharmacology , Pyridazines/pharmacokinetics , Pyridazines/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Dipeptidyl peptidase IV (DPP4) inhibitors are emerging as a new class of therapeutic agents for the treatment of type 2 diabetes. They exert their beneficial effects by increasing the levels of active glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are two important incretins for glucose homeostasis. Starting from a high-throughput screening hit, we were able to identify a series of piperidinone- and piperidine-constrained phenethylamines as novel DPP4 inhibitors. Optimized compounds are potent, selective, and have good pharmacokinetic profiles.
Subject(s)
Adenosine Deaminase Inhibitors , Dipeptidyl-Peptidase IV Inhibitors , Glycoproteins/antagonists & inhibitors , Phenethylamines/chemical synthesis , Piperidines/chemical synthesis , Animals , Biological Availability , Crystallography, X-Ray , Dipeptidyl Peptidase 4 , Humans , Molecular Conformation , Phenethylamines/pharmacokinetics , Phenethylamines/pharmacology , Piperidines/pharmacokinetics , Piperidines/pharmacology , Piperidones/chemical synthesis , Piperidones/pharmacokinetics , Piperidones/pharmacology , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A preliminary safety evaluation of ACC2 inhibitor 1-(S) revealed serious neurological and cardiovascular liabilities of this chemotype. A systematic structure-toxicity relationship study identified the alkyne linker as the key motif responsible for these adverse effects. Toxicogenomic studies in rats showed that 1-(R) and 1-(S) induced gene expression patterns similar to that seen with several known cardiotoxic agents such as doxorubicin. Replacement of the alkyne with alternative linker groups led to a new series of ACC inhibitors with drastically improved cardiovascular and neurological profiles.
Subject(s)
Acetyl-CoA Carboxylase/antagonists & inhibitors , Blood Pressure/drug effects , Heart Rate/drug effects , Seizures/chemically induced , Thiazoles/chemical synthesis , Administration, Oral , Animals , Gene Expression/drug effects , Infusions, Intravenous , Male , Myocardium/metabolism , Oligonucleotide Array Sequence Analysis , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Thiazoles/adverse effects , Thiazoles/chemistryABSTRACT
A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes. The cyclohexene ring of lead-like screening hit 5 was replaced with a pyrrolidine to enable parallel chemistry, and protein co-crystal structural data guided the optimization of N-substituents. Employing this strategy, a >400x improvement in potency over the initial hit was realized in rapid fashion. Optimized compounds are potent and selective inhibitors with excellent pharmacokinetic profiles. Compound 30 was efficacious in vivo, lowering blood glucose in ZDF rats that were allowed to feed freely on a mixed meal.
Subject(s)
Chemistry, Pharmaceutical/methods , Dipeptidyl-Peptidase IV Inhibitors , Enzyme Inhibitors/chemical synthesis , Phenethylamines/chemical synthesis , Pyrrolidines/chemical synthesis , Animals , Blood Glucose/metabolism , Cyclohexenes/chemistry , Diabetes Mellitus, Type 2/drug therapy , Drug Design , Enzyme Inhibitors/chemistry , Female , Hypoglycemic Agents/pharmacology , Models, Chemical , Molecular Conformation , Phenethylamines/chemistry , Pyrrolidines/chemistry , RatsABSTRACT
Starting from a rapidly metabolized adamantane 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor 22a, a series of E-5-hydroxy-2-adamantamine inhibitors, exemplified by 22d and (+/-)-22f, was discovered. Many of these compounds are potent inhibitors of 11beta-HSD1 and are selective over 11beta-HSD2 for multiple species (human, mouse, and rat), unlike other reported species-selective series. These compounds have good cellular potency and improved microsomal stability. Pharmacokinetic profiling in rodents indicated moderate to large volumes of distribution, short half-lives, and a pharmacokinetic species difference with the greatest exposure measured in rat with 22d. One hour postdose liver, adipose, and brain tissue 11beta-HSD1 inhibition was confirmed with (+/-)-22f in a murine ex vivo assay. Although 5,7-disubstitued-2-adamantamines provided greater stability, a single, E-5-position, polar functional group afforded inhibitors with the best combination of stability, potency, and selectivity. These results indicate that adamantane metabolic stabilization sufficient to obtain short-acting, potent, and selective 11beta-HSD1 inhibitors has been discovered.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Adamantane/analogs & derivatives , Adamantane/chemical synthesis , Piperazines/chemical synthesis , 11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics , Adamantane/pharmacokinetics , Animals , Cell Line , Humans , In Vitro Techniques , Mice , Microsomes, Liver/metabolism , Piperazines/pharmacokinetics , Rats , Stereoisomerism , Structure-Activity Relationship , Tissue DistributionABSTRACT
The hemodynamic effects of a series of potent and selective 4-aminopyridine carboxamide-based pan-JNK inhibitors were assessed in an anesthetized rat model. The effects of these agents on mean arterial pressure, heart rate, cardiac contractility, and peripheral vascular resistance are described, and the implication for targeting protein kinases in metabolic diseases is discussed.
Subject(s)
Blood Pressure/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Heart Rate/drug effects , MAP Kinase Kinase 4/antagonists & inhibitors , Metabolic Diseases/drug therapy , Metabolic Diseases/enzymology , Myocardial Contraction/drug effects , Vascular Resistance/drug effects , Aminopyridines/chemical synthesis , Aminopyridines/pharmacology , Anesthesia , Anesthetics , Animals , Male , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Thiopental/analogs & derivatives , Ventricular Function, Left/drug effectsABSTRACT
The incorporation of constrained tertiary amines into an existing class of N-benzyl-4-aminopiperidinyl chromone-based MCHr1 antagonists led to the identification of a series of chiral racemic compounds that displayed good to excellent functional potency, binding affinity, and selectivity over the hERG channel. Further separation of two distinct chiral racemic compounds into their corresponding pairs of enantiomers revealed a considerable selectivity for MCHr1 for one configuration, in addition to a striking difference in oral exposure between one pair of enantiomers in diet-induced obese mice. Oral administration of the most potent compound in this class in the same animal model led to significant reduction of fat mass in a semi-chronic model for weight loss.
Subject(s)
Chromones/chemical synthesis , Chromones/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Animals , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacology , Appetite Depressants/pharmacology , Body Weight/drug effects , Brain/metabolism , Cell Line , Diet , Dietary Fats , Ether-A-Go-Go Potassium Channels/drug effects , Fenfluramine/pharmacology , Indicators and Reagents , Mice , Molecular Conformation , Potassium Channel Blockers/chemical synthesis , Potassium Channel Blockers/pharmacology , Structure-Activity RelationshipABSTRACT
A novel class of adamantane ethers 11beta-hydroxysteroid hydrogenase type I inhibitors has been discovered. These compounds have excellent HSD-1 potency and selectivity against HSD-2. The structure-activity relationships, selectivity, metabolism, PK, ex vivo pharmacodynamic data, and an X-ray crystal structure of one of these inhibitors bound to h-HSD-1 are discussed.