ABSTRACT
To further explore the optimum placement of the acid moiety in conformationally constrained analogs of GW 4064 1a, a series of stilbene replacements were prepared. The benzothiophene 1f and the indole 1g display the optimal orientation of the carboxylate for enhanced FXR agonist potency.
Subject(s)
Isoxazoles/chemistry , Isoxazoles/pharmacology , Receptors, Cytoplasmic and Nuclear/agonists , Stilbenes/chemistry , Stilbenes/pharmacology , Amino Acid Sequence , Animals , Cell Line , Humans , Molecular Conformation , Molecular Sequence Data , Receptors, Cytoplasmic and Nuclear/metabolismABSTRACT
To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes.
Subject(s)
Isoxazoles/chemistry , Naphthalenes/chemistry , Quinolines/chemistry , Receptors, Cytoplasmic and Nuclear/agonists , Animals , Binding Sites , Blood Glucose/metabolism , Crystallography, X-Ray , Diabetes Mellitus, Experimental/metabolism , Dogs , Fluorescence Resonance Energy Transfer , Humans , Isoxazoles/chemical synthesis , Isoxazoles/pharmacokinetics , Ligands , Mice , Molecular Conformation , Protein Structure, Tertiary , Quinolines/chemical synthesis , Quinolines/pharmacokinetics , Rats , Receptors, Cytoplasmic and Nuclear/metabolism , Weight Gain/drug effectsABSTRACT
Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.
Subject(s)
Isoxazoles/chemistry , Naphthalenes/chemistry , Receptors, Cytoplasmic and Nuclear/agonists , Thiophenes/chemistry , Animals , Binding Sites , Computer Simulation , Crystallography, X-Ray , Humans , Isoxazoles/pharmacology , Naphthalenes/pharmacokinetics , Rats , Receptors, Cytoplasmic and Nuclear/metabolism , Structure-Activity Relationship , Thiophenes/pharmacokineticsABSTRACT
Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.
Subject(s)
Isoxazoles/chemical synthesis , Receptors, Cytoplasmic and Nuclear/agonists , Animals , Crystallography, X-Ray , Fluorescence Resonance Energy Transfer , Isoxazoles/chemistry , Isoxazoles/pharmacology , Rats , Receptors, Cytoplasmic and Nuclear/metabolism , Structure-Activity RelationshipABSTRACT
Inhibition of acetyl-CoA carboxylase (ACC) may prevent lipid-induced insulin resistance and type 2 diabetes, making the enzyme an attractive pharmaceutical target. Although the enzyme is highly conserved amongst animals, only the yeast enzyme structure is available for rational drug design. The use of biophysical assays has permitted the identification of a specific C-terminal truncation of the 826-residue human ACC2 carboxyl transferase (CT) domain that is both functionally competent to bind inhibitors and crystallizes in their presence. This C-terminal truncation led to the determination of the human ACC2 CT domain-CP-640186 complex crystal structure, which revealed distinctions from the yeast-enzyme complex. The human ACC2 CT-domain C-terminus is comprised of three intertwined alpha-helices that extend outwards from the enzyme on the opposite side to the ligand-binding site. Differences in the observed inhibitor conformation between the yeast and human structures are caused by differing residues in the binding pocket.
Subject(s)
Acetyl-CoA Carboxylase/chemistry , Acetyl-CoA Carboxylase/antagonists & inhibitors , Acetyl-CoA Carboxylase/isolation & purification , Acetyl-CoA Carboxylase/metabolism , Acetyltransferases/antagonists & inhibitors , Amino Acid Sequence , Binding Sites , Circular Dichroism , Crystallography, X-Ray , Fatty Acids/metabolism , Fluorescence Polarization , Humans , Ligands , Models, Molecular , Molecular Sequence Data , Protein Conformation , Protein Denaturation , Protein Structure, Tertiary , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/isolation & purification , Recombinant Fusion Proteins/metabolism , Saccharomyces cerevisiae Proteins/chemistry , Sequence Alignment , Sequence Homology, Amino Acid , Species Specificity , Structure-Activity RelationshipABSTRACT
A series of estrogen receptor ligands based on a 3-alkyl naphthalene scaffold was synthesized using an intramolecular enolate-alkyne cycloaromatization as the key step. Several of these compounds bearing a C6-OH group were shown to be high affinity ligands. All compounds had similar ERalpha and ERbeta binding affinity ranging from micromolar to low nanomolar.
Subject(s)
Naphthalenes/chemical synthesis , Naphthalenes/pharmacology , Receptors, Estrogen/agonists , Combinatorial Chemistry Techniques , Estrogen Receptor Modulators/metabolism , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/metabolism , Female , Humans , Ligands , Molecular Structure , Naphthalenes/chemistry , Selective Estrogen Receptor Modulators/metabolism , Structure-Activity RelationshipABSTRACT
We report the synthesis and in vitro activity of a series of novel pyrrolidinyl pyridones and pyrazinones as potent inhibitors of prolyl oligopeptidase (POP). Within this series, compound 39 was co-crystallized within the catalytic site of a human chimeric POP protein which provided a more detailed understanding of how these inhibitors interacted with the key residues within the catalytic pocket.
Subject(s)
Pyridones/chemical synthesis , Pyridones/pharmacology , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Serine Endopeptidases/drug effects , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacology , Brain/drug effects , Brain/metabolism , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Drug Design , Humans , Molecular Conformation , Molecular Structure , Prolyl Oligopeptidases , Pyridones/blood , Pyridones/chemistry , Pyrrolidines/blood , Pyrrolidines/chemistry , Serine Proteinase Inhibitors/blood , Serine Proteinase Inhibitors/chemistryABSTRACT
Starting from the known FXR agonist GW 4064 1a, a series of stilbene replacements were prepared. The 6-substituted 1-naphthoic acid 1b was an equipotent FXR agonist with improved developability parameters relative to 1a. Analog 1b also reduced the severity of cholestasis in the ANIT acute cholestatic rat model.
Subject(s)
Carboxylic Acids/chemical synthesis , Carboxylic Acids/pharmacology , Cholestasis/drug therapy , DNA-Binding Proteins/agonists , Isoxazoles/chemical synthesis , Isoxazoles/pharmacology , Naphthalenes/chemical synthesis , Naphthalenes/pharmacology , Receptors, Cytoplasmic and Nuclear/agonists , Transcription Factors/agonists , Administration, Oral , Animals , Carboxylic Acids/chemistry , Cholestasis/metabolism , Cholestasis/pathology , Crystallography, X-Ray , DNA-Binding Proteins/chemistry , Disease Models, Animal , Dogs , Gastric Mucosa/metabolism , Haplorhini , Isoxazoles/chemistry , Mice , Molecular Conformation , Molecular Structure , Naphthalenes/chemistry , Rats , Receptors, Cytoplasmic and Nuclear/chemistry , Stomach/drug effects , Structure-Activity Relationship , Transcription Factors/chemistryABSTRACT
Explorations of the S(1') subsite of ACE2 via modifications of the P(1') methylene biphenyl moiety of thiol-based metalloprotease inhibitors led to improvements in ACE2 selectivity versus ACE and NEP, while maintaining potent ACE2 inhibition.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/chemistry , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Peptidyl-Dipeptidase A/metabolism , Sulfhydryl Compounds/chemistry , Sulfhydryl Compounds/pharmacology , Angiotensin-Converting Enzyme 2 , Binding Sites , Humans , Models, Molecular , Molecular Structure , Recombinant Proteins , Structure-Activity RelationshipABSTRACT
Screening of a metalloprotease library led to the identification of a thiol-based dual ACE/NEP inhibitor as a potent ACE2 inhibitor. Modifications of the P(1) benzyl moiety led to improvements in ACE2 potency as well as to increased selectivity versus ACE and NEP.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/chemistry , Peptidyl-Dipeptidase A/drug effects , Sulfhydryl Compounds/chemistry , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/metabolism , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Female , Male , Mice , Mice, Inbred C57BL , Peptidyl-Dipeptidase A/genetics , Structure-Activity Relationship , Substrate Specificity , Sulfhydryl Compounds/metabolism , Sulfhydryl Compounds/pharmacologyABSTRACT
The estrogen-related receptor alpha (ERRalpha) is a potential target for activation in the treatment of metabolic disease. To date, no small-molecule agonists of ERRalpha have been identified despite several high-throughput screening campaigns. We describe the synthesis and profiling of a small array of compounds designed on the basis of a previously reported agonist-bound crystal structure of the closely related receptor ERRgamma. The results suggest that ERRalpha may be intractable as a direct target for pharmacologic activation.
Subject(s)
Hydrazones/chemistry , Hydrazones/pharmacology , Receptors, Estrogen/agonists , Receptors, Estrogen/chemistry , Binding Sites , Crystallography, X-Ray , Drug Inverse Agonism , Fluorescence Resonance Energy Transfer , HeLa Cells , Humans , Hydrazones/chemical synthesis , Receptors, Estrogen/antagonists & inhibitors , ERRalpha Estrogen-Related ReceptorABSTRACT
Starting from a potent ketone-based inhibitor with poor drug properties, incorporation of P(2)-P(3) elements from a ketoamide-based inhibitor led to the identification of a hybrid series of ketone-based cathepsin K inhibitors with better oral bioavailability than the starting ketone.
Subject(s)
Cathepsins/antagonists & inhibitors , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/pharmacokinetics , Ketones/chemistry , Ketones/pharmacokinetics , Administration, Oral , Biological Availability , Cathepsin K , Cathepsins/chemistry , Crystallography, X-Ray , Cysteine Proteinase Inhibitors/administration & dosage , Humans , Ketones/administration & dosage , Protein Conformation , Structure-Activity RelationshipABSTRACT
X-ray crystal structures of the ligand binding domain (LBD) of the estrogen-related receptor-gamma (ERRgamma) were determined that describe this receptor in three distinct states: unliganded, inverse agonist bound, and agonist bound. Two structures were solved for the unliganded state, the ERRgamma LBD alone, and in complex with a coregulator peptide representing a portion of receptor interacting protein 140 (RIP140). No significant differences were seen between these structures that both exhibited the conformation of ERRgamma seen in studies with other coactivators. Two structures were obtained describing the inverse agonist-bound state, the ERRgamma LBD with 4-hydroxytamoxifen (4-OHT), and the ERRgamma LBD with 4-OHT and a peptide representing a portion of the silencing mediator of retinoid and thyroid hormone action protein (SMRT). The 4-OHT structure was similar to other reported inverse agonist bound structures, showing reorientation of phenylalanine 435 and a displacement of the AF-2 helix relative to the unliganded structures with little other rearrangement occurring. No significant changes to the LBD appear to be induced by peptide binding with the addition of the SMRT peptide to the ERRgamma plus 4-OHT complex. The observed agonist-bound state contains the ERRgamma LBD, a ligand (GSK4716), and the RIP140 peptide and reveals an unexpected rearrangement of the phenol-binding residues. Thermal stability studies show that agonist binding leads to global stabilization of the ligand binding domain. In contrast to the conventional mechanism of nuclear receptor ligand activation, activation of ERRgamma by GSK4716 does not appear to involve a major rearrangement or significant stabilization of the C-terminal helix.
Subject(s)
Receptors, Cytoplasmic and Nuclear/chemistry , Receptors, Estrogen/chemistry , Binding Sites , Circular Dichroism , Crystallography, X-Ray , Humans , In Vitro Techniques , Ligands , Models, Molecular , Multiprotein Complexes , Protein Structure, Quaternary , Protein Structure, Tertiary , Receptors, Cytoplasmic and Nuclear/agonists , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Estrogen/agonists , Receptors, Estrogen/genetics , Receptors, Estrogen/metabolism , Recombinant Proteins/agonists , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Static ElectricityABSTRACT
Starting from a potent pantolactone ketoamide cathepsin K inhibitor discovered from structural screening, conversion of the lactone scaffold to a pyrrolidine scaffold allowed exploration of the S(3) subsite of cathepsin K. Manipulation of P3 and P1' groups afforded potent inhibitors with drug-like properties.
Subject(s)
Amides , Cathepsins/antagonists & inhibitors , Cysteine Proteinase Inhibitors , Ketones , Pyrrolidines , Amides/chemical synthesis , Amides/pharmacokinetics , Amides/pharmacology , Binding Sites , Cathepsin K , Cathepsins/chemistry , Crystallography, X-Ray , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/pharmacokinetics , Cysteine Proteinase Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Ketones/chemical synthesis , Ketones/pharmacokinetics , Ketones/pharmacology , Models, Molecular , Molecular Structure , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacokinetics , Pyrrolidines/pharmacology , Serine Proteinase Inhibitors , Structure-Activity RelationshipABSTRACT
Starting from potent aldehyde inhibitors with poor drug properties, derivatization to semicarbazones led to the identification of a series of semicarbazone-based cathepsin K inhibitors with greater solubility and better pharmacokinetic profiles than their parent aldehydes. Furthermore, a representative semicarbazone inhibitor attenuated bone resorption in an ex vivo rat calvarial bone resorption model. However, based on enzyme inhibition comparisons at neutral pH, semicarbazone hydrolysis rates, and 13C NMR experiments, these semicarbazones probably function as prodrugs of aldehydes.
Subject(s)
Aldehydes/chemistry , Cathepsins/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Semicarbazones/pharmacology , Animals , Cathepsin K , Crystallography, X-Ray , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Hydrogen-Ion Concentration , Hydrolysis , Models, Molecular , Molecular Conformation , Prodrugs/chemical synthesis , Prodrugs/chemistry , Prodrugs/pharmacology , Rats , Semicarbazones/chemical synthesis , Semicarbazones/chemistry , Solubility , Structure-Activity RelationshipABSTRACT
The design and synthesis of 4-hydroxytamoxifen (4-OHT) derivatives are described. The binding affinities of these compounds toward the orphan estrogen-related receptor gamma and the classical estrogen receptor alpha demonstrate that analogs bearing hydroxyalkyl groups display improved binding selectivity profiles compared with that of 4-OHT. An X-ray crystal structure of one of the designed compounds bound to ERRgamma LBD confirms the molecular basis of the selectivity.
Subject(s)
Receptors, Cytoplasmic and Nuclear/drug effects , Receptors, Estrogen/drug effects , Tamoxifen , Binding Sites/drug effects , Crystallography, X-Ray , Drug Design , Estrogen Receptor alpha/drug effects , Humans , Ligands , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Tamoxifen/analogs & derivatives , Tamoxifen/chemical synthesis , Tamoxifen/pharmacologyABSTRACT
Ketoheterocyclic inhibitors of cathepsin K have been disclosed. SAR of potency enhancing P2-P3 groups coupled with ketoheterocyclic warheads to provide cathepsin K inhibitors have been described. In addition, a novel route to access alpha-ketothiazoles using a key thioamide functionality has been disclosed. The mild method employed allows for the presence of diverse functional groups, such as amide and carbamate functionalities, commonly found in protease inhibitors that have peptidomimetic scaffolds. This new method should provide a quick entry into functionally diverse protease inhibitors.
Subject(s)
Cathepsins/antagonists & inhibitors , Heterocyclic Compounds/chemical synthesis , Binding Sites , Cathepsin B/antagonists & inhibitors , Cathepsin K , Cathepsin L , Cysteine Endopeptidases , Heterocyclic Compounds/pharmacology , Humans , Hydrogen Bonding , Inhibitory Concentration 50 , Protein Binding , Recombinant Proteins , Structure-Activity RelationshipABSTRACT
An orally bioavailable series of ketoamide-based cathepsin K inhibitors with good pharmacokinetic properties has been identified. Starting from a potent inhibitor endowed with poor drug properties, conformational constraint of the P(2)-P(3) linker and modifications to P(1') elements led to an enhancement in potency, solubility, clearance, and bioavailability. These optimized inhibitors attenuated bone resorption in a rat TPTX hypocalcemic bone resorption model.
Subject(s)
Amides/chemical synthesis , Cathepsins/antagonists & inhibitors , Cysteine Proteinase Inhibitors/chemical synthesis , Ketones/chemical synthesis , Amides/pharmacokinetics , Amides/pharmacology , Animals , Binding Sites , Biological Availability , Bone Resorption/drug therapy , Bone Resorption/metabolism , Cathepsin K , Cathepsins/chemistry , Cysteine Proteinase Inhibitors/pharmacokinetics , Cysteine Proteinase Inhibitors/pharmacology , Disease Models, Animal , Hypocalcemia/drug therapy , Hypocalcemia/metabolism , Ketones/pharmacokinetics , Ketones/pharmacology , Rats , Rats, Wistar , Solubility , Structure-Activity RelationshipABSTRACT
Conversion of the proline-derived cyanamide lead to an acyclic cyanamide capable of forming an additional hydrogen bond with cathepsin K resulted in a large increase in inhibitory activity. An X-ray structure of a co-crystal of a cyanamide with cathepsin K confirmed the enzyme interaction. Furthermore, a representative acyclic cyanamide inhibitor 6r was able to attenuate bone resorption in the rat calvarial model.
Subject(s)
Cathepsins/antagonists & inhibitors , Cyanamide/chemistry , Cysteine Proteinase Inhibitors/pharmacology , Osteogenesis/drug effects , Animals , Binding Sites , Bone Resorption , Cathepsin B/antagonists & inhibitors , Cathepsin H , Cathepsin K , Cathepsin L , Crystallography, X-Ray , Cysteine Endopeptidases , Cysteine Proteinase Inhibitors/chemical synthesis , Disease Models, Animal , Humans , Hydrogen Bonding , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Protein Binding , Rats , Recombinant Proteins/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
The first small molecule agonists of the estrogen-related receptors have been identified. GSK4716 (3) and GSK9089 (4) show binding to ERRgamma with remarkable selectivity over the classical estrogen receptors. Notably, in cell-based reporter assays, 3 mimics the protein ligand PGC-1alpha in activation of human ERRbeta and ERRgamma.