ABSTRACT
Models of atherosclerosis are used in preclinical studies but often fail to translate to humans. A model that better reflects human atherosclerosis is necessary. We recently engineered the ExeGen™ low-density lipoprotein receptor (LDLR) miniswine, in which the LDL receptor gene is modified to drive hypercholesterolemia and atherosclerosis, and showed diet-related exacerbation of these phenotypes. Five groups of animals, either wild type (+/+) or heterozygous (+/-), were fed either a normal or high-fat diet for 6 months. One group of heterozygous pigs fed a high-fat diet was also administered atorvastatin at 3 mg/kg/day. Clinical chemistry and anatomic pathology parameters were measured biweekly and at termination. The high-fat diet resulted in increased adiposity and interspersion of adipocytes within the salivary glands. The heterozygous pigs on the high-fat diet gained more weight and had significant increases in total cholesterol, high-density lipoprotein, and LDL compared to wild-type animals or heterozygous animals fed a normal diet. Atorvastatin attenuated these parameters, indicating the statin had a beneficial effect, even in a high-fat diet scenario. Atorvastatin treatment also reduced the intensity of Oil Red O staining in pigs on high-fat diet. Atorvastatin-related amelioration of several indices of cardiovascular pathophysiology in this model underscores its utility for drug discovery.
Subject(s)
Disease Models, Animal , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Hypercholesterolemia , Receptors, LDL/genetics , Translational Research, Biomedical/methods , Animals , Animals, Genetically Modified , Aorta/drug effects , Aorta/pathology , Atherosclerosis , Atorvastatin/pharmacology , Atorvastatin/therapeutic use , Diet, High-Fat , Femoral Artery/drug effects , Femoral Artery/pathology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hypercholesterolemia/drug therapy , Hypercholesterolemia/metabolism , Hypercholesterolemia/pathology , Swine , Swine, MiniatureABSTRACT
Development of effective vaccines against emerging infectious diseases (EID) can take as much or more than a decade to progress from pathogen isolation/identification to clinical approval. As a result, conventional approaches fail to produce field-ready vaccines before the EID has spread extensively. Lassa is a prototypical emerging infectious disease endemic to West Africa for which no successful vaccine is available. We established the VaxCelerate Consortium to address the need for more rapid vaccine development by creating a platform capable of generating and pre-clinically testing a new vaccine against specific pathogen targets in less than 120 d A self-assembling vaccine is at the core of the approach. It consists of a fusion protein composed of the immunostimulatory Mycobacterium tuberculosis heat shock protein 70 (MtbHSP70) and the biotin binding protein, avidin. Mixing the resulting protein (MAV) with biotinylated pathogen-specific immunogenic peptides yields a self-assembled vaccine (SAV). To meet the time constraint imposed on this project, we used a distributed R&D model involving experts in the fields of protein engineering and production, bioinformatics, peptide synthesis/design and GMP/GLP manufacturing and testing standards. SAV immunogenicity was first tested using H1N1 influenza specific peptides and the entire VaxCelerate process was then tested in a mock live-fire exercise targeting Lassa fever virus. We demonstrated that the Lassa fever vaccine induced significantly increased class II peptide specific interferon-γ CD4(+) T cell responses in HLA-DR3 transgenic mice compared to peptide or MAV alone controls. We thereby demonstrated that our SAV in combination with a distributed development model may facilitate accelerated regulatory review by using an identical design for each vaccine and by applying safety and efficacy assessment tools that are more relevant to human vaccine responses than current animal models.
Subject(s)
Avidin/immunology , Bacterial Proteins/immunology , HSP70 Heat-Shock Proteins/immunology , Lassa Fever/immunology , Lassa Fever/prevention & control , Viral Vaccines/immunology , Animals , Avidin/therapeutic use , Bacterial Proteins/therapeutic use , CD4-Positive T-Lymphocytes/immunology , Communicable Diseases, Emerging/prevention & control , Female , HLA-DR3 Antigen/genetics , HSP70 Heat-Shock Proteins/therapeutic use , Influenza A Virus, H1N1 Subtype/immunology , Interferon-gamma/immunology , Lassa virus/immunology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mycobacterium tuberculosis/immunology , Ovalbumin/immunology , Protein Engineering , Recombinant Fusion Proteins/immunology , Recombinant Fusion Proteins/therapeutic use , Viral Vaccines/therapeutic useABSTRACT
Continuing studies based on dihydroquinoline glucocorticoid receptor agonists lead to the discovery of a series of C4-oxime analogs. Representative compounds exhibited potent transrepression activity with minimal transactivation of phosphoenolpyruvate caboxykinase (PEPCK), a key protein in the gluconeogenesis pathway. These compounds represent promising leads in identifying GR agonists with high anti-inflammatory activity and attenuated potential for glucose elevation.
Subject(s)
Carboxy-Lyases/metabolism , Quinolines/pharmacology , Receptors, Glucocorticoid/agonists , Enzyme Activation , Quinolines/chemistry , Structure-Activity RelationshipABSTRACT
A series of tetrahydroquinoline derivatives were synthesized and profiled for their ability to act as glucocorticoid receptor selective modulators. Structure-activity relationships of the tetrahydroquinoline B-ring lead to the discovery of orally available GR-selective agonists with high in vivo activity.
Subject(s)
Quinolines/pharmacology , Receptors, Glucocorticoid/agonists , Administration, Oral , Animals , Drug Discovery , Enzyme-Linked Immunosorbent Assay , Humans , Quinolines/administration & dosage , Quinolines/chemistry , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Continuing studies on tetrahydroquinoline glucocorticoid receptor anti-inflammatory agents lead to the identification of several tetrahydroquinolin-3-yl carbamates that exhibited steroid-like activity in in vitro transrepression assays with reduced transactivation of phosphoenol pyruvate carboxykinase (PEPCK), a key enzyme in the gluconeogenesis pathway.
Subject(s)
Carboxy-Lyases/metabolism , Quinolines/pharmacology , Receptors, Glucocorticoid/agonists , Enzyme ActivationABSTRACT
We have previously disclosed a series of glucocorticoid receptor (GR) ligands derived from 6-indole-1,2,3,4-tetrahydroquinolines through structure-activity relationship (SAR) of the pendent C6-indole ring. In parallel with this effort, we now report SAR of the tetrahydroquinoline A-ring that identified the importance of a C3 hydroxyl in improving GR selectivity within a series of non-steroidal GR agonists.
Subject(s)
Quinolines/chemistry , Receptors, Glucocorticoid/agonists , Drug Evaluation, Preclinical , Protein Binding , Quinolines/chemical synthesis , Quinolines/pharmacology , Receptors, Glucocorticoid/metabolism , Structure-Activity RelationshipABSTRACT
Throughout the centuries, traditional Chinese medicine has been a rich resource in the development of new drugs. Modern drug discovery, which relies increasingly on automated high throughput screening and quick hit-to-lead development, however, is confronted with the challenges of the chemical complexity associated with natural products. New technologies for biological screening as well as library building are in great demand in order to meet the requirements. Here we review the developments in these techniques under the perspective of their applicability in natural product drug discovery. Methods in library building, component characterizing, biological evaluation, and other screening methods including NMR and X-ray diffraction are discussed.
Subject(s)
Biological Products/chemistry , Biological Products/pharmacology , Drug Evaluation, Preclinical/methods , High-Throughput Screening Assays/methods , Medicine, Chinese Traditional , Animals , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/pharmacology , Humans , Plants, Medicinal/chemistryABSTRACT
Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (K(i)=13.2nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids for the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.
Subject(s)
Gluconeogenesis/drug effects , Indoles/pharmacology , Liver/drug effects , Receptors, Glucocorticoid/antagonists & inhibitors , Xanthenes/pharmacology , Active Transport, Cell Nucleus/drug effects , Cell Line , Cell Nucleus/metabolism , Dexamethasone/antagonists & inhibitors , Dexamethasone/pharmacology , Gene Expression/drug effects , Gluconeogenesis/genetics , Humans , Indoles/chemistry , Liver/metabolism , Matrix Metalloproteinase 9/metabolism , Receptors, Glucocorticoid/metabolism , Xanthenes/chemistryABSTRACT
Recent clinical trials with bisphosphonates and PTH have not supported the hypothesis that combination treatments with antiresorptive and anabolic agents would lead to synergistic activity. We hypothesized that combination treatment with a selective androgen receptor modulator (SARM), LGD-3303, and a bisphosphonate would be beneficial. In vitro competitive binding and transcriptional activity assays were used to characterize LGD-3303. LGD-3303 is a potent nonsteroidal androgen that shows little or no cross-reactivity with related nuclear receptors. Tissue selective activity of LGD-3303 was assessed in orchidectomized male rats orally administered LGD-3303 for 14 days. LGD-3303 increased the levator ani muscle weight above eugonadal levels but had greatly reduced activity on the prostate, never increasing the ventral prostate weight to >50% of eugonadal levels even at high doses. Ovariectomized female rats were treated with LGD-3303, alendronate, or combination treatment to study the effects on bone. DXA scans, histomorphometry, and biomechanics were performed. LGD-3303 increased muscle weight in females rats. In addition, LGD-3303 increased BMD and BMC at both cortical and cancellous bone sites. At cortical sites, the effects were caused in part by anabolic activity on the periosteal surface. At every measured site, combination treatment was as effective as either single agent and in some cases showed significant added benefit. LGD-3303 is a novel SARM with anabolic effects on muscle and cortical bone not observed with bisphosphonates. Combination therapy with LGD-3303 and alendronate had additive effects and may potentially be a useful therapy for osteoporosis and frailty.
Subject(s)
Androgen Antagonists/therapeutic use , Bone Diseases, Metabolic/drug therapy , Diphosphonates/therapeutic use , Absorptiometry, Photon , Androgen Antagonists/pharmacology , Animals , Biomechanical Phenomena/drug effects , Body Weight/drug effects , Bone Density/drug effects , Bone Diseases, Metabolic/blood , Bone Diseases, Metabolic/physiopathology , Diphosphonates/pharmacology , Drug Synergism , Drug Therapy, Combination , Estrogens/deficiency , Female , Femur/drug effects , Femur/pathology , Femur/physiopathology , Lumbar Vertebrae/drug effects , Lumbar Vertebrae/pathology , Lumbar Vertebrae/physiopathology , Male , Orchiectomy , Organ Size/drug effects , Osteocalcin/blood , Ovariectomy , Pyrroles/pharmacology , Pyrroles/therapeutic use , Quinolones/pharmacology , Quinolones/therapeutic use , Rats , Rats, Sprague-Dawley , Transcription, Genetic/drug effectsABSTRACT
A series of nonsteroidal glucocorticoid receptor (GR) ligands based on a 6-indole-1,2,3,4-tetrahydroquinoline scaffold are reported. Structure-activity relationship (SAR) of the pendent indole group identified compound 20 exhibiting good GR binding affinity (K(i)=1.5nM) and 100- to 1000-fold selectivity over MR, PR, and AR while showing activity in an E-selectin repression assay.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Indoles/pharmacology , Quinolines/pharmacology , Receptors, Glucocorticoid/drug effects , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Binding Sites , Drug Evaluation, Preclinical , Indoles/chemical synthesis , Indoles/chemistry , Ligands , Molecular Structure , Quinolines/chemical synthesis , Quinolines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The progesterone receptor plays an important role in the female reproductive system. Here we describe the discovery of a new selective progesterone receptor modulator (SPRM). In rats, the lead compound, 7,9-difluoro-5-(3-methylcyclohex-2-enyl)-2,2,4-trimethyl-1,2-dihydrochromeno[3,4- f]quinoline ( 5c), inhibited ovulation and showed full efficacy in uterine and vaginal tissue but was a mixed partial agonist/antagonist in breast tissue. The compound also suppressed ovulation in monkeys, but in contrast to currently approved steroidal PR agonists, it did not suppress estradiol levels.
Subject(s)
Benzopyrans/chemical synthesis , Benzopyrans/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Receptors, Progesterone/antagonists & inhibitors , Animals , Benzopyrans/chemistry , Female , Haplorhini , Humans , Molecular Structure , Ovulation/drug effects , Quinolines/chemistry , Rats , Receptors, Progesterone/metabolism , Structure-Activity RelationshipABSTRACT
Glucocorticoids are commonly used antiinflammatory agents whose use is limited by side effects. We have developed a series of glucocorticoid receptor (GR) ligands that retain the strong antiinflammatory activity of conventional glucocorticoids with reduced side effects. We present a compound, LGD5552, that binds the receptor efficiently and strongly represses inflammatory gene expression. LGD5552 bound to GR activates gene expression somewhat differently than glucocorticoids. It activates some genes with an efficacy similar to that of the glucocorticoids. However, other glucocorticoid-activated genes are not regulated by LGD5552. These differences may be because of the more efficient binding of corepressor in the presence of LGD5552, compared with glucocorticoid agonists. This class of nonsteroidal, GR-dependent antiinflammatory drugs may offer a safer alternative to steroidal glucocorticoids in the treatment of inflammatory disease.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Arthritis, Experimental/drug therapy , Arthritis, Rheumatoid/drug therapy , Benzopyrans/pharmacology , Benzylidene Compounds/pharmacology , Glucocorticoids/pharmacology , Receptors, Glucocorticoid/antagonists & inhibitors , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Benzopyrans/chemistry , Benzopyrans/therapeutic use , Benzylidene Compounds/chemistry , Benzylidene Compounds/therapeutic use , Cell Line, Tumor , Gene Expression/drug effects , Glucocorticoids/chemistry , Glucocorticoids/therapeutic use , Ligands , Mice , Mice, Inbred Strains , Osteogenesis/drug effects , Rats , Receptors, Glucocorticoid/metabolismABSTRACT
Structure-activity relationship studies centered around 3'-substituted (Z)-5-(2'-(thienylmethylidene))1,2-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5H-chromeno[3,4-f]quinolines are described. A series of highly potent and efficacious selective glucocorticoid receptor modulators were identified with in vitro activity comparable to dexamethasone. In vivo evaluation of these compounds utilizing a 28 day mouse tumor xenograft model demonstrated efficacy equal to dexamethasone in the reduction of tumor volume.
Subject(s)
Antineoplastic Agents/chemical synthesis , Benzopyrans/chemical synthesis , Multiple Myeloma/drug therapy , Quinolines/chemical synthesis , Receptors, Glucocorticoid/drug effects , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzopyrans/chemistry , Benzopyrans/pharmacology , Binding, Competitive , Dexamethasone/pharmacology , Humans , Mice , Mineralocorticoid Receptor Antagonists , Models, Molecular , Multiple Myeloma/pathology , Quinolines/chemistry , Quinolines/pharmacology , Receptors, Glucocorticoid/agonists , Receptors, Glucocorticoid/antagonists & inhibitors , Receptors, Mineralocorticoid/agonists , Stereoisomerism , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Recent interest in orally available androgens has fueled the search for new androgens for use in hormone replacement therapy and as anabolic agents. In pursuit of this, we have discovered a series of novel androgen receptor modulators derived from 7H-[1,4]oxazino[3,2-g]quinolin-7-ones. These compounds were synthesized and evaluated in competitive binding assays and an androgen receptor transcriptional activation assay. A number of compounds from the series demonstrated single-digit nanomolar agonist activity in vitro. In addition, lead compound (R)-16e was orally active in established rodent models that measure androgenic and anabolic properties of these agents. In this assay, (R)-16e demonstrated full efficacy in muscle and only partially stimulated the prostate at 100 mg/kg. These data suggest that these compounds may be utilized as selective androgen receptor modulators or SARMs. This series represents a novel class of compounds for use in androgen replacement therapy.
Subject(s)
Oxazines/chemical synthesis , Quinolones/chemical synthesis , Receptors, Androgen/drug effects , Anabolic Agents/chemical synthesis , Anabolic Agents/chemistry , Anabolic Agents/pharmacology , Androgens , Animals , Binding, Competitive , Cell Line, Tumor , Humans , Male , Muscle, Skeletal/anatomy & histology , Muscle, Skeletal/drug effects , Organ Size/drug effects , Oxazines/chemistry , Oxazines/pharmacology , Prostate/anatomy & histology , Prostate/drug effects , Quinolones/chemistry , Quinolones/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Transcriptional Activation/drug effectsABSTRACT
Specific retinoid X receptor (RXR) agonists, such as LG100268 (LG268), and the thiazolidinedione (TZD) PPARgamma agonists, such as rosiglitazone, produce insulin sensitization in rodent models of insulin resistance and type 2 diabetes. In sharp contrast to the TZDs that produce significant increases in body weight gain, RXR agonists reduce body weight gain and food consumption. Unfortunately, RXR agonists also suppress the thyroid hormone axis and generally produce hypertriglyceridemia. Heterodimer-selective RXR modulators have been identified that, in rodents, retain the metabolic benefits of RXR agonists with reduced side effects. These modulators bind specifically to RXR with high affinity and are RXR homodimer partial agonists. Although RXR agonists activate many heterodimer partners, these modulators selectively activate RXR:PPARalpha and RXR:PPARgamma, but not RXR:RARalpha, RXR:LXRalpha, RXR:LXRbeta, or RXR:FXRalpha. We report the in vivo characterization of one RXR modulator, LG101506 (LG1506). In Zucker fatty (fa/fa) rats, LG1506 is a potent insulin sensitizer that also enhances the insulin-sensitizing activities of rosiglitazone. Administration of LG1506 reduces both body weight gain and food consumption and blocks the TZD-induced weight gain when coadministered with rosiglitazone. LG1506 does not significantly suppress the thyroid hormone axis in rats, nor does it elevate triglycerides in Sprague Dawley rats. However, LG1506 produces a unique pattern of triglycerides elevation in Zucker rats. LG1506 elevates high-density lipoprotein cholesterol in humanized apolipoprotein A-1-transgenic mice. Therefore, selective RXR modulators are a promising approach for developing improved therapies for type 2 diabetes, although additional studies are needed to understand the strain-specific effects on triglycerides.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Fatty Acids, Unsaturated/administration & dosage , Hypoglycemic Agents/administration & dosage , Obesity/drug therapy , Phenyl Ethers/administration & dosage , Retinoid X Receptors/agonists , Thiazolidinediones/administration & dosage , Analysis of Variance , Animals , Apolipoprotein A-I/genetics , Apolipoprotein A-I/physiology , Area Under Curve , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/complications , Dose-Response Relationship, Drug , Drug Interactions , Female , Hypoglycemic Agents/therapeutic use , Mice , Mice, Transgenic , Obesity/blood , Obesity/complications , PPAR gamma/agonists , PPAR gamma/metabolism , Rats , Rats, Sprague-Dawley , Rats, Zucker , Retinoid X Receptors/metabolism , Rosiglitazone , Statistics, Nonparametric , Thiazolidinediones/pharmacology , Thiazolidinediones/therapeutic use , Thyroid Gland/drug effects , Triglycerides/bloodABSTRACT
To understand the species selectivity in a series of alpha-methyl-alpha-phenoxy carboxylic acid PPARalpha/gamma dual agonists (1-11), structure-based molecular modeling was carried out in the ligand binding pockets of both human and mouse PPARalpha. This study suggested that interaction of both 4-phenoxy and phenyloxazole substituents of these ligands with F272 and M279 in mouse PPARalpha leads to the species-specific divergence in ligand binding. Insights obtained in the molecular modeling studies of these key interactions resulted in the ability to convert a human-selective PPARalpha agonist to a human and mouse dual agonist within the same platform.
Subject(s)
Cinnamates/chemical synthesis , Models, Molecular , PPAR alpha/agonists , Animals , Cinnamates/chemistry , Cinnamates/pharmacology , Drug Design , Humans , Ligands , Mice , Molecular Structure , Species Specificity , Structure-Activity RelationshipABSTRACT
The design and synthesis of the dual peroxisome proliferator activated receptor (PPAR) alpha/gamma agonist (S)-2-methyl-3-[4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)ethoxy]phenyl]-2-phenoxypropionic acid (2) for the treatment of type 2 diabetes and associated dyslipidemia are described. 2 possesses a potent dual hPPAR alpha/gamma agonist profile (IC(50) = 28 and 10 nM; EC(50) = 9 and 4 nM, respectively, for hPPARalpha and hPPARgamma). In preclinical models, 2 substantially improves insulin sensitivity and potently reverses diabetic hyperglycemia while significantly improving overall lipid homeostasis.
Subject(s)
Hypoglycemic Agents/chemical synthesis , Hypolipidemic Agents/chemical synthesis , Phenylpropionates/chemical synthesis , Receptors, Cytoplasmic and Nuclear/agonists , Thiophenes/chemical synthesis , Transcription Factors/agonists , Animals , Binding, Competitive , Cell Line , Diabetes Mellitus, Type 2/drug therapy , Female , Humans , Hyperlipidemias/drug therapy , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Hypolipidemic Agents/chemistry , Hypolipidemic Agents/pharmacology , Phenylpropionates/chemistry , Phenylpropionates/pharmacology , Radioligand Assay , Rats , Rats, Zucker , Stereoisomerism , Structure-Activity Relationship , Thiophenes/chemistry , Thiophenes/pharmacologyABSTRACT
A series of 5-benylidene-1,2-dihydrochromeno[3,4-f]quinolines (4) were synthesized and tested in bioassays to evaluate their progestational activities, receptor- and tissue-selectivity profiles as selective progesterone receptor modulators (SPRMs). Most of the new analogues exhibited as highly potent progestins with more than 100-fold receptor selectivity over other steroid hormone receptors and LG120920 (7b) demonstrated tissue selectivity toward uterus and vagina versus breasts in a rodent model after oral administration.
Subject(s)
Benzylidene Compounds/chemistry , Benzylidene Compounds/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Receptors, Progesterone/antagonists & inhibitors , Androgen Receptor Antagonists , Animals , Benzylidene Compounds/metabolism , Binding, Competitive , Breast Neoplasms/metabolism , Cell Division/drug effects , Cells, Cultured , Chlorocebus aethiops , Epithelial Cells/cytology , Epithelial Cells/drug effects , Estrone/antagonists & inhibitors , Estrone/pharmacology , Female , Humans , Mammary Glands, Animal/cytology , Mammary Glands, Animal/drug effects , Medroxyprogesterone Acetate/metabolism , Medroxyprogesterone Acetate/pharmacology , Progesterone/metabolism , Progesterone/pharmacology , Progesterone Congeners/chemistry , Progesterone Congeners/metabolism , Progesterone Congeners/pharmacology , Quinolines/chemical synthesis , Rats , Receptors, Androgen/metabolism , Receptors, Glucocorticoid/antagonists & inhibitors , Receptors, Glucocorticoid/metabolism , Receptors, Progesterone/metabolism , Structure-Activity Relationship , Uterus/cytology , Uterus/drug effects , Vagina/cytology , Vagina/drug effectsABSTRACT
A series of 5-methylidene 1,2-dihydrochromeno[3,4-f]quinoline derivatives were synthesized and tested in biological assays to evaluate scope and limitations of the nonsteroidal SPRM pharmacophore (3). A number of orally available highly potent nonsteroidal modulators were identified by modification of the substituents at 5-methylidene position.
Subject(s)
Quinolines/chemical synthesis , Quinolines/pharmacology , Receptors, Progesterone/agonists , Receptors, Progesterone/antagonists & inhibitors , Administration, Oral , Animals , Cell Division/drug effects , Cell Line , Chlorocebus aethiops , Epithelial Cells/cytology , Epithelial Cells/drug effects , Estradiol/pharmacology , Female , Humans , Inhibitory Concentration 50 , Progesterone/pharmacology , Quinolines/chemistry , Rats , Receptors, Progesterone/metabolism , Receptors, Steroid/antagonists & inhibitors , Structure-Activity Relationship , Transcription, Genetic/drug effects , Transfection , Uterus/cytology , Uterus/drug effectsABSTRACT
A series of 1,2-dihydrochromeno[3,4-f]quinoline derivatives was synthesized and tested in biological assays to evaluate the nonsteroidal progesterone receptor modulator pharmacophore (4) as antiprogestins. A number of potent analogues were identified by modification of the substituents at the D-ring.