ABSTRACT
The continued development of computational and synthetic methods has enabled the enumeration or preparation of a nearly endless universe of chemical structures. Nevertheless, the ability of this chemical universe to deliver small molecules that can both modulate biological targets and have drug-like physicochemical properties continues to be a topic of interest to the pharmaceutical industry and academic researchers alike. The chemical space described by public, commercial, in-house and virtual compound collections has been interrogated by multiple approaches including biochemical, cellular and virtual screening, diversity analysis, and in-silico profiling. However, current drugs and known chemical probes derived from these efforts are contained within a remarkably small volume of the predicted chemical space. Access to more diverse classes of chemical scaffolds that maintain the properties relevant for drug discovery is certainly needed to meet the increasing demands for pharmaceutical innovation. The Lilly Open Innovation Drug Discovery platform (OIDD) was designed to tackle barriers to innovation through the identification of novel molecules active in relevant disease biology models. In this article we will discuss several computational approaches towards describing novel, biologically active, drug-like chemical space and illustrate how the OIDD program may facilitate access to previously untapped molecules that may aid in the search for innovative pharmaceuticals.
Subject(s)
Drug Discovery/methods , Computational Biology , HumansABSTRACT
A novel, potent series of indole analogs were recently developed as MR antagonists, culminating in 14. This compound represents the first MR antagonist in this class of molecules, exhibiting picomolar binding affinity and in vivo blood pressure lowering at pharmaceutically relevant doses.
Subject(s)
Antihypertensive Agents/chemical synthesis , Indoles/chemical synthesis , Mineralocorticoid Receptor Antagonists , Sulfonamides/chemical synthesis , Animals , Antihypertensive Agents/chemistry , Antihypertensive Agents/pharmacology , Crystallography, X-Ray , Indoles/chemistry , Indoles/pharmacology , Models, Molecular , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
The design and synthesis of a novel piperidine series of farnesyltransferase (FTase) inhibitors with reduced potential for metabolic glucuronidation are described. The various substitution and exchange of the phenyl group at the C-2 position of the previously described 2-(4-hydroxy)phenyl-3-nitropiperidine 1a (FTase IC(50)=5.4nM) resulted in metabolically stable compounds with potent FTase inhibition (14a IC(50)=4.3nM, 20a IC(50)=3.0nM, and 50a IC(50)=16nM). Molecular modeling studies of these compounds complexed with FTase and farnesyl pyrophosphate are also described.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/pharmacology , Glucuronides/metabolism , Piperidines/chemical synthesis , Animals , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Mice , Microsomes, Liver/metabolism , Models, Molecular , Molecular Structure , Piperidines/chemistry , Piperidines/pharmacology , Protein Prenylation , Rats , Structure-Activity RelationshipABSTRACT
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
Syntheses and SAR studies of 3,3-bisaryloxindole analogues provided potent mineralocorticoid receptor (MR) antagonists that were selective over other steroid nuclear hormone receptors.
Subject(s)
Indoles/pharmacology , Mineralocorticoid Receptor Antagonists , Humans , Radioligand AssayABSTRACT
The synthesis and in vitro characterization of novel RXR-selective ligands possessing various substituted 1-benzofuran or 1-benzothiophene moieties are described.
Subject(s)
Drug Design , Receptors, Retinoic Acid/metabolism , Transcription Factors/metabolism , Tretinoin/analogs & derivatives , Tretinoin/metabolism , Protein Binding/physiology , Retinoid X Receptors , Structure-Activity RelationshipABSTRACT
New RXR-selective modulators possessing a 6-fluoro trienoic acid moiety (6Z olefin) or a fluorinated/heterocyclic-substituted benzene core ring, were synthesized in an expedient and selective way. A subset of these compounds was evaluated for their metabolic properties (exposure in IRC male mice) and show a dramatic increase of exposure compared to our reference compound, 3 (LG101506).
Subject(s)
Coumarins/chemical synthesis , Coumarins/pharmacology , Receptors, Retinoic Acid/physiology , Transcription Factors/physiology , Animals , Binding, Competitive , Cell Line , Drug Design , Kinetics , Male , Mice , Receptors, Retinoic Acid/drug effects , Retinoic Acid Receptor alpha , Retinoid X Receptors , Transcription Factors/drug effects , Tretinoin/pharmacokinetics , Retinoic Acid Receptor gammaABSTRACT
Retinoid X receptor:peroxisome proliferative-activated receptor (RXR:PPAR) heterodimers play a critical role in the regulation of glucose (RXR/PPARgamma) and lipid metabolism (RXR/PPARalpha). Previously, we described a concise structure-activity relationship study of selective RXR modulators possessing a (2E,4E,6Z)-3-methyl-7-(3,5-dialkyl-6-alkoxyphenyl)-octa-2,4,6-trienoic acid scaffold. These studies were focused on the 2-position alkoxy side chain. We describe here the design and synthesis of a novel series of RXR selective modulators possessing the same aromatic core structure with the addition of a ring locked 6-7-Z-olefin on the trienoic acid moiety. The synthesis and structure-activity relationship studies of these 6,7-locked cyclopentenyl, phenyl, thienyl, furan, and pyridine-trienoic acid derivatives is presented herein.
Subject(s)
Benzene Derivatives/chemistry , Benzene Derivatives/pharmacology , Caprylates/chemistry , Caprylates/pharmacology , Thiazolidinediones , Alkenes/chemistry , Alkenes/pharmacology , Animals , Benzene Derivatives/chemical synthesis , Caprylates/chemical synthesis , Cell Line , Chlorocebus aethiops , Dose-Response Relationship, Drug , Drug Design , Drug Synergism , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Male , Mice , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Retinoic Acid/agonists , Receptors, Retinoic Acid/antagonists & inhibitors , Receptors, Retinoic Acid/genetics , Receptors, Retinoic Acid/metabolism , Retinoid X Receptors , Rosiglitazone , Structure-Activity Relationship , Thiazoles/pharmacology , Thyroxine/blood , Transcription Factors/agonists , Transcription Factors/antagonists & inhibitors , Transcription Factors/genetics , Transcription Factors/metabolism , Transfection , Triglycerides/bloodABSTRACT
Fenofibrate is clinically successful in treating hypertriglyceridemia and mixed hyperlipidemia presumably through peroxisome proliferator-activated receptor alpha (PPARalpha)-dependent induction of genes that control fatty acid beta-oxidation. Lipid homeostasis and cholesterol metabolism also are regulated by the nuclear oxysterol receptors, liver X receptors alpha and beta (LXRalpha and LXRbeta). Here we show that fenofibrate ester, but not fenofibric acid, functions as an LXR antagonist by directly binding to LXRs. Likewise, ester forms, but not carboxylic acid forms, of other members of the fibrate class of molecules antagonize the LXRs. The fibrate esters display greater affinity for LXRs than the corresponding fibric acids have for PPARalpha. Thus, these two nuclear receptors display a degree of conservation in their recognition of ligands; yet, the acid/ester moiety acts as a chemical switch that determines PPARalpha versus LXR specificity. Consistent with its LXR antagonistic activity, fenofibrate potently represses LXR agonist-induced transcription of hepatic lipogenic genes. Surprisingly, fenofibrate does not repress LXR-induced transcription of various ATP-binding cassette transporters either in liver or in macrophages, suggesting that fenofibrate manifests variable biocharacter in the context of differing gene promoters. These findings provide not only an unexpected mechanism by which fenofibrate inhibits lipogenesis but also the basis for examination of the pharmacology of an LXR ligand in humans.
Subject(s)
ATP-Binding Cassette Transporters , Receptors, Cytoplasmic and Nuclear/metabolism , Transcription Factors/metabolism , Adenosine Triphosphate/metabolism , Animals , Anticholesteremic Agents/pharmacology , Bacterial Proteins/metabolism , Carrier Proteins/metabolism , DNA-Binding Proteins , Dose-Response Relationship, Drug , Fenofibrate/pharmacology , Humans , Hydrocarbons, Fluorinated , Hypolipidemic Agents/pharmacology , Inhibitory Concentration 50 , Ligands , Lipid Metabolism , Liver/metabolism , Liver/pathology , Liver X Receptors , Mice , Models, Chemical , Orphan Nuclear Receptors , Protein Binding , Reverse Transcriptase Polymerase Chain Reaction , Scintillation Counting , Sulfonamides , Time Factors , Transcriptional Activation , Transfection , Tumor Cells, CulturedABSTRACT
Retinoid X receptor (RXR) modulators are being evaluated as a means for the treatment of non-insulin dependent (type II) diabetes mellitus, and substantial progress has been made in the preclinical evaluation of these compounds. To aid in this process, several structural classes of RXR modulators are now under investigation. The diverse structures and syntheses of these compounds will be discussed in this review.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Drug Delivery Systems/methods , Receptors, Retinoic Acid/metabolism , Retinoids/therapeutic use , Transcription Factors/metabolism , Animals , Diabetes Mellitus, Type 2/metabolism , Humans , Receptors, Retinoic Acid/agonists , Receptors, Retinoic Acid/antagonists & inhibitors , Retinoid X Receptors , Retinoids/chemistry , Retinoids/metabolism , Transcription Factors/agonists , Transcription Factors/antagonists & inhibitorsABSTRACT
The selective estrogen receptor modulator arzoxifene and the rexinoid LG 100268 were active not only as single agents for prevention and treatment of breast cancer in the rat model that uses nitrosomethylurea as the carcinogen but also showed striking synergy, both preventively and therapeutically, in a series of six experiments with a total of 465 rats. Mechanistic studies in cell culture reported here suggest that enhancement of stromal-epithelial interactions may contribute to this synergy. The possible clinical use of the combination of arzoxifene and LG 100268 for prevention of breast cancer in women at high risk, for treatment of women in the adjuvant setting, or for treatment of end-stage disease should now be considered.