ABSTRACT
Through an internal virtual screen at GlaxoSmithKline a distinct class of 2-phenylimidazo[1,2-a]pyridine-6-carboxamide H-PGDS inhibitors were discovered. Careful evaluation of crystal structures and SAR led to a novel, potent, and orally active imidazopyridine inhibitor of H-PGDS, 20b. Herein, describes the identification of 2 classes of inhibitors, their syntheses, and their challenges.
Subject(s)
Drug Discovery , Enzyme Inhibitors/pharmacology , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Intramolecular Oxidoreductases/antagonists & inhibitors , Intramolecular Oxidoreductases/metabolism , Molecular Structure , Structure-Activity RelationshipABSTRACT
GlaxoSmithKline and Astex Pharmaceuticals recently disclosed the discovery of the potent H-PGDS inhibitor GSK2894631A 1a (IC50 = 9.9 nM) as part of a fragment-based drug discovery collaboration with Astex Pharmaceuticals. This molecule exhibited good murine pharmacokinetics, allowing it to be utilized to explore H-PGDS pharmacology in vivo. Yet, with prolonged dosing at higher concentrations, 1a induced CNS toxicity. Looking to attenuate brain penetration in this series, aza-quinolines, were prepared with the intent of increasing polar surface area. Nitrogen substitutions at the 6- and 8-positions of the quinoline were discovered to be tolerated by the enzyme. Subsequent structure activity studies in these aza-quinoline scaffolds led to the identification of 1,8-naphthyridine 1y (IC50 = 9.4 nM) as a potent peripherally restricted H-PGDS inhibitor. Compound 1y is efficacious in four in vivo inflammatory models and exhibits no CNS toxicity.
Subject(s)
Aza Compounds/chemistry , Enzyme Inhibitors/chemistry , Quinolines/chemistry , Animals , Binding Sites , Brain/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Crystallography, X-Ray , Drug Stability , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Humans , Intramolecular Oxidoreductases/antagonists & inhibitors , Intramolecular Oxidoreductases/metabolism , Kinetics , Male , Mice , Mice, Inbred C57BL , Molecular Dynamics Simulation , Muscle, Skeletal/chemistry , Muscle, Skeletal/metabolism , Rats , Structure-Activity RelationshipABSTRACT
With the goal of discovering more selective anti-inflammatory drugs, than COX inhibitors, to attenuate prostaglandin signaling, a fragment-based screen of hematopoietic prostaglandin D synthase was performed. The 76 crystallographic hits were sorted into similar groups, with the 3-cyano-quinoline 1a (FP IC50â¯=â¯220,000â¯nM, LEâ¯=â¯0.43) being a potent member of the 6,6-fused heterocyclic cluster. Employing SAR insights gained from structural comparisons of other H-PGDS fragment binding mode clusters, the initial hit 1a was converted into the 70-fold more potent quinoline 1d (IC50â¯=â¯3,100â¯nM, LEâ¯=â¯0.49). A systematic substitution of the amine moiety of 1d, utilizing structural information and array chemistry, with modifications to improve inhibitor stability, resulted in the identification of the 300-fold more active H-PGDS inhibitor tool compound 1bv (IC50â¯=â¯9.9â¯nM, LEâ¯=â¯0.42). This selective inhibitor exhibited good murine pharmacokinetics, dose-dependently attenuated PGD2 production in a mast cell degranulation assay and should be suitable to further explore H-PGDS biology.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Intramolecular Oxidoreductases/antagonists & inhibitors , Lipocalins/antagonists & inhibitors , Quinolines/chemistry , Quinolines/pharmacology , Animals , Drug Discovery , Enzyme Inhibitors/pharmacokinetics , Humans , Intramolecular Oxidoreductases/chemistry , Intramolecular Oxidoreductases/metabolism , Lipocalins/chemistry , Lipocalins/metabolism , Male , Mice, Inbred C57BL , Molecular Docking Simulation , Quinolines/pharmacokineticsABSTRACT
Starting from 4-amino-8-quinoline carboxamide lead 1a and scaffold hopping to the chemically more tractable quinazoline, a systematic exploration of the 2-substituents of the quinazoline ring, utilizing structure activity relationships and conformational constraint, resulted in the identification of 39 novel CD38 inhibitors. Eight of these analogs were 10-100-fold more potent human CD38 inhibitors, including the single digit nanomolar inhibitor 1am. Several of these molecules also exhibited improved therapeutic indices relative to hERG activity. A representative analog 1r exhibited suitable pharmacokinetic parameters for in vivo animal studies, including moderate clearance and good oral bioavailability. These inhibitor compounds will aid in the exploration of the enzymatic functions of CD38, as well as furthering the study of the therapeutic implications of NAD enhancement in metabolic disease models.
Subject(s)
ADP-ribosyl Cyclase 1/antagonists & inhibitors , Amides/chemistry , Enzyme Inhibitors/chemistry , NAD/metabolism , Quinazolines/chemistry , ADP-ribosyl Cyclase 1/metabolism , Amides/metabolism , Amides/pharmacokinetics , Animals , Binding Sites , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacokinetics , Half-Life , Humans , Mice , Molecular Docking Simulation , NAD/chemistry , Protein Structure, Tertiary , Structure-Activity RelationshipABSTRACT
Starting from the micromolar 8-quinoline carboxamide high-throughput screening hit 1a, a systematic exploration of the structure-activity relationships (SAR) of the 4-, 6-, and 8-substituents of the quinoline ring resulted in the identification of approximately 10-100-fold more potent human CD38 inhibitors. Several of these molecules also exhibited pharmacokinetic parameters suitable for in vivo animal studies, including low clearances and decent oral bioavailability. Two of these CD38 inhibitors, 1ah and 1ai, were shown to elevate NAD tissue levels in liver and muscle in a diet-induced obese (DIO) C57BL/6 mouse model. These inhibitor tool compounds will enable further biological studies of the CD38 enzyme as well as the investigation of the therapeutic implications of NAD enhancement in disease models of abnormally low NAD.
Subject(s)
ADP-ribosyl Cyclase 1/antagonists & inhibitors , Amides/chemistry , Aminoquinolines/chemistry , NAD/metabolism , Quinolines/chemistry , Amides/chemical synthesis , Amides/pharmacology , Aminoquinolines/chemical synthesis , Aminoquinolines/pharmacology , Animals , Biological Availability , Crystallography, X-Ray , Humans , Hydrolysis , Liver/metabolism , Membranes, Artificial , Mice, Inbred C57BL , Models, Molecular , Muscle, Skeletal/metabolism , Obesity/metabolism , Permeability , Protein Conformation , Quinolines/chemical synthesis , Quinolines/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of thiazoloquin(az)olinones were synthesized and found to have potent inhibitory activity against CD38. Several of these compounds were also shown to have good pharmacokinetic properties and demonstrated the ability to elevate NAD levels in plasma, liver, and muscle tissue. In particular, compound 78c was given to diet induced obese (DIO) C57Bl6 mice, elevating NAD > 5-fold in liver and >1.2-fold in muscle versus control animals at a 2 h time point. The compounds described herein possess the most potent CD38 inhibitory activity of any small molecules described in the literature to date. The inhibitors should allow for a more detailed assessment of how NAD elevation via CD38 inhibition affects physiology in NAD deficient states.
Subject(s)
ADP-ribosyl Cyclase 1/antagonists & inhibitors , Quinolones/chemistry , Quinolones/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacology , ADP-ribosyl Cyclase 1/metabolism , Animals , Cell Line , Dogs , Drug Discovery , Humans , Liver/drug effects , Liver/metabolism , Mice, Inbred C57BL , Molecular Docking Simulation , Muscles/drug effects , Muscles/metabolism , NAD/analysis , NAD/blood , NAD/metabolism , Obesity/drug therapy , Obesity/metabolism , Quinolones/chemical synthesis , Quinolones/pharmacokinetics , Thiazoles/chemical synthesis , Thiazoles/pharmacokineticsABSTRACT
The farnesoid X receptor (FXR) may play a crucial role in a number of metabolic diseases and, as such, could potentially serve as a target for the development of therapeutics as a treatment for those diseases. Previous work has described GW4064 as an FXR agonist with an interesting activity profile. This manuscript will describe the synthesis of novel analogs of GW4064 and the activity profile of those analogs.
Subject(s)
Isoxazoles/chemistry , Isoxazoles/pharmacology , Oxazolidinones/pharmacology , Receptors, Cytoplasmic and Nuclear/agonists , Drug Evaluation, Preclinical , Fluorescence Resonance Energy Transfer , Humans , Models, Molecular , Molecular Structure , Oxazolidinones/chemistry , Structure-Activity RelationshipABSTRACT
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
Starting from a weak omeprazole screening hit, replacement of the pyridine with a 1,3-benzodioxole moiety, modification of the thioether linkage, and substitution of the benzimidazole pharmacophore led to the discovery of nanomolar BRS-3 agonists.
Subject(s)
Omeprazole/chemistry , Receptors, Bombesin/agonists , Baculoviridae/metabolism , Benzimidazoles/chemistry , Brain/metabolism , Chemistry, Pharmaceutical/methods , Chlorofluorocarbons, Methane/chemistry , Drug Design , Drug Evaluation, Preclinical , Humans , Kinetics , Models, Chemical , Pyridines/chemistry , Receptors, Bombesin/chemistry , Sulfides/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 design, synthesis, and SAR of a novel series of heterobiaryl phenethanolamine beta3 adrenergic receptor agonists are described. The furan analogue 49 was shown to elicit a significant dose-dependent lowering of plasma glucose in a rodent model of type 2 diabetes.
Subject(s)
Adrenergic beta-3 Receptor Agonists , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Binding Sites , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
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
The synthesis of a series of phenethanolamine aniline agonists that contain an aniline ring on the right-hand side of the molecule substituted at the meta position with a benzoic acid or a pyridyl carboxylate is described. Several of the analogues (e.g., 34, 36-38, 40, and 44) have high beta(3) adrenergic receptor (AR) potency and selectivity against beta(1) and beta(2) ARs in Chinese hamster ovary (CHO) cells expressing beta ARs. The dog pharmacokinetic profile of some of these analogues showed >25% oral bioavailability and po half-lives of at least 1.5 h. Among the compounds described herein, the 3,3'-biarylaniline carboxylate derivatives 36, 38 and the phenylpyridyl derivative 44 demonstrated outstanding in vitro properties and reasonable dog pharmacokinetic profiles. These three analogues also showed dose dependent beta(3) AR mediated responses in mice. The ease of synthesis and superior dog pharmacokinetics of compound 38 relative to that of 44 in combination with its in vitro profile led us to choose this compound as a development candidate for the treatment of type 2 diabetes.
Subject(s)
Adrenergic beta-3 Receptor Agonists , Aniline Compounds/chemistry , Ethanolamine/chemistry , Ethanolamine/pharmacology , Receptors, Adrenergic, beta-3/metabolism , Animals , Blood Glucose/metabolism , Cell Line , Cricetinae , Cyclic AMP/metabolism , Dogs , Ethanolamine/chemical synthesis , Glycosylation/drug effects , Hemoglobins/metabolism , Humans , Male , Mice , Molecular Structure , Structure-Activity RelationshipABSTRACT
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.
