ABSTRACT
Riboswitches are non-coding RNA structures located in messenger RNAs that bind endogenous ligands, such as a specific metabolite or ion, to regulate gene expression. As such, riboswitches serve as a novel, yet largely unexploited, class of emerging drug targets. Demonstrating this potential, however, has proven difficult and is restricted to structurally similar antimetabolites and semi-synthetic analogues of their cognate ligand, thus greatly restricting the chemical space and selectivity sought for such inhibitors. Here we report the discovery and characterization of ribocil, a highly selective chemical modulator of bacterial riboflavin riboswitches, which was identified in a phenotypic screen and acts as a structurally distinct synthetic mimic of the natural ligand, flavin mononucleotide, to repress riboswitch-mediated ribB gene expression and inhibit bacterial cell growth. Our findings indicate that non-coding RNA structural elements may be more broadly targeted by synthetic small molecules than previously expected.
Subject(s)
Pyrimidines/chemistry , Pyrimidines/pharmacology , RNA, Bacterial/chemistry , RNA, Bacterial/drug effects , Riboswitch/drug effects , Animals , Aptamers, Nucleotide/chemistry , Bacteria/cytology , Bacteria/drug effects , Bacteria/growth & development , Base Sequence , Crystallography, X-Ray , Escherichia coli Infections/drug therapy , Escherichia coli Infections/microbiology , Escherichia coli Proteins/genetics , Female , Flavin Mononucleotide/metabolism , Gene Expression Regulation, Bacterial/drug effects , Heat-Shock Proteins/genetics , Intramolecular Transferases/genetics , Ligands , Mice , Mice, Inbred DBA , Models, Molecular , Molecular Sequence Data , Pyrimidines/isolation & purification , Pyrimidines/therapeutic use , RNA, Bacterial/genetics , Reproducibility of Results , Riboflavin/biosynthesis , Riboswitch/genetics , Substrate SpecificityABSTRACT
Imidazo-[1, 2-a]pyrazine 1 is a potent inhibitor of Aurora A and B kinase in vitro and is effective in in vivo tumor models, but has poor oral bioavailbility and is unsuitable for oral dosing. We describe herein our effort to improve oral exposure in this class, resulting ultimately in the identification of a potent Aurora inhibitor 16, which exhibited good drug exposure levels across species upon oral dosing, and showed excellent in vivo efficacy in a mouse xenograft tumor model when dosed orally.
Subject(s)
Antineoplastic Agents/therapeutic use , Aurora Kinase A/antagonists & inhibitors , Aurora Kinase B/antagonists & inhibitors , Imidazoles/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyrazines/therapeutic use , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Dogs , HCT116 Cells , Haplorhini , Histones/metabolism , Humans , Imidazoles/administration & dosage , Imidazoles/chemical synthesis , Imidazoles/pharmacokinetics , Mice , Phosphorylation , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Pyrazines/administration & dosage , Pyrazines/chemical synthesis , Pyrazines/pharmacokinetics , Rats , Stereoisomerism , Xenograft Model Antitumor AssaysABSTRACT
A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized to improve the profile of the previous lead compound 1. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. The optimization efforts allowed the identification of 33, a quinoline amide exhibiting potent Na(v)1.7 inhibitory activity and moderate selectivity over Na(v)1.5. Compound 33 displayed anti-nociceptive oral efficacy in a rat CFA inflammatory pain model at 100 mpk and in a rat spinal nerve ligation neuropathic pain model with an EC50 75 µM.
Subject(s)
Analgesics/pharmacology , Ganglia, Spinal/drug effects , NAV1.7 Voltage-Gated Sodium Channel/chemistry , Neuralgia/drug therapy , Sodium Channel Blockers/pharmacology , Spinal Nerves/drug effects , Spiro Compounds/pharmacology , Analgesics/chemistry , Animals , Molecular Structure , Patch-Clamp Techniques , Quinoxalines/chemistry , Rats , Sodium Channel Blockers/chemistry , Spiro Compounds/chemistry , Structure-Activity RelationshipABSTRACT
A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized and displayed potent Nav1.7 inhibitory activity and moderate selectivity over Nav1.5. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. Compound 41 displayed anti-nociceptive efficacy in the rat CFA pain model at 100 mpk oral dosing.
Subject(s)
Drug Discovery , NAV1.7 Voltage-Gated Sodium Channel/metabolism , Quinoxalines/pharmacology , Sodium Channel Blockers/pharmacology , Spiro Compounds/pharmacology , Dose-Response Relationship, Drug , Humans , Molecular Structure , Quinoxalines/chemical synthesis , Quinoxalines/chemistry , Sodium Channel Blockers/chemical synthesis , Sodium Channel Blockers/chemistry , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Structure-Activity RelationshipABSTRACT
Isoxazoles are frequently used amide isosteres, as shown in the context of discovery of CRTh2 antagonists from amide 1 to isoxazole 2. However, persistent agonism and poor solubility in isoxazole series presented challenges to its further development. Based on the concept of quality by design (QbD), 5,5-disubstituted isoxazolines 3 were introduced. The chirality at 5 position of isoxazolines controlled the switch between two modes of actions, which led to a novel series of pure antagonists. This non-planar motif also conferred a change of shape of these molecules, which avoided flat structures and improved their physical properties.
Subject(s)
Amides/chemistry , Drug Design , Isoxazoles/chemistry , Quinazolinones/chemistry , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Animals , Dogs , Half-Life , Haplorhini , Humans , Isoxazoles/chemical synthesis , Isoxazoles/pharmacokinetics , Quinazolinones/chemical synthesis , Quinazolinones/pharmacokinetics , Rats , Rats, Wistar , Receptors, Immunologic/metabolism , Receptors, Prostaglandin/metabolism , Solubility , Structure-Activity RelationshipABSTRACT
A series of pyrazoloquinoline analogs have been synthesized and shown to bind to PDE10 with high affinity. From the SAR study and our lead optimization efforts, compounds 16 and 27 were found to possess potent oral antipsychotic activity in the MK-801 induced hyperactive rat model.
Subject(s)
Antipsychotic Agents/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/chemistry , Pyrazoles/pharmacology , Quinolines/pharmacology , Schizophrenia/drug therapy , Administration, Oral , Animals , Chemistry, Pharmaceutical/methods , Crystallography, X-Ray/methods , Disease Models, Animal , Dizocilpine Maleate/pharmacology , Drug Design , Excitatory Amino Acid Antagonists/pharmacology , Humans , Models, Chemical , Molecular Conformation , Rats , Structure-Activity RelationshipABSTRACT
The identification of potent and orally active dihydroimidazoisoquinolines as PDE 10A inhibitors is reported. The SAR development led to the discovery of compound 35 as a potent, selective, and orally active PDE10A inhibitor. Compound 35 inhibited MK-801-induced hyperactivity at 3mg/kg and displayed a 10-fold separation between the minimal effective doses for inhibition of MK-801-induced hyperactivity and hypolocomotion in rats.
Subject(s)
Hyperkinesis/drug therapy , Imidazoles/chemical synthesis , Isoquinolines/chemical synthesis , Phosphodiesterase Inhibitors/chemical synthesis , Phosphoric Diester Hydrolases/chemistry , Psychotropic Drugs/chemical synthesis , Animals , Area Under Curve , Crystallography, X-Ray , Cyclic Nucleotide Phosphodiesterases, Type 3/chemistry , Cyclic Nucleotide Phosphodiesterases, Type 3/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 7/chemistry , Cyclic Nucleotide Phosphodiesterases, Type 7/metabolism , Dizocilpine Maleate , Haplorhini , Humans , Hyperkinesis/chemically induced , Hyperkinesis/enzymology , Imidazoles/administration & dosage , Imidazoles/pharmacokinetics , Isoquinolines/administration & dosage , Isoquinolines/pharmacokinetics , Male , Models, Molecular , Phosphodiesterase Inhibitors/administration & dosage , Phosphodiesterase Inhibitors/pharmacokinetics , Phosphoric Diester Hydrolases/metabolism , Psychotropic Drugs/administration & dosage , Psychotropic Drugs/pharmacokinetics , Rats , Schizophrenia/drug therapy , Schizophrenia/enzymology , Structure-Activity RelationshipABSTRACT
High-throughput screening identified a series of pyrazoloquinolines as PDE10A inhibitors. The SAR development led to the discovery of compound 27 as a potent, selective, and orally active PDE10A inhibitor. Compound 27 inhibits MK-801 induced hyperactivity at 3mg/kg with an ED(50) of 4mg/kg and displays a â¼6-fold separation between the ED(50) for inhibition of MK-801 induced hyperactivity and hypolocomotion in rats.
Subject(s)
Enzyme Inhibitors/pharmacology , Phosphoric Diester Hydrolases/metabolism , Pyrazolones/pharmacology , Quinolines/pharmacology , Schizophrenia/drug therapy , Administration, Oral , Animals , Crystallography, X-Ray , Dizocilpine Maleate/antagonists & inhibitors , Dizocilpine Maleate/pharmacology , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , High-Throughput Screening Assays , Humans , Models, Molecular , Molecular Structure , Pyrazolones/administration & dosage , Pyrazolones/chemistry , Quinolines/administration & dosage , Quinolines/chemistry , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of spiro-azetidines and azetidinones has been evaluated as novel blockers of the T-type calcium channel (Ca(V)3.2) which is a new therapeutic target for the potential treatment of both inflammatory and neuropathic pain. Confirmation and optimization of the potency, selectivity and DMPK properties of leads will be described.
Subject(s)
Azetidines/chemistry , Calcium Channel Blockers/chemical synthesis , Calcium Channels, T-Type/chemistry , Piperidines/chemistry , Spiro Compounds/chemistry , Animals , Azetidines/chemical synthesis , Azetidines/therapeutic use , Calcium Channel Blockers/chemistry , Calcium Channel Blockers/therapeutic use , Calcium Channels, T-Type/metabolism , Drug Design , Humans , Pain/drug therapy , Protein Binding , Rats , Structure-Activity RelationshipABSTRACT
Herein, we disclose three structurally differentiated γ-secretase modulators (GSMs) based on an oxadiazine scaffold. The analogues from series I potently inhibit the generation of Aß42 in vitro when the substituents at 3 and 4 positions of the oxadiazine moiety adopt an α orientation (cf. 11). To address the concern around potential reactivity of the exocyclic double bond present in series I toward nucleophilic attack, compounds containing either an endocyclic double bond, such as 20 (series II), or devoid of an olefinic moiety, such as 27 (series III), were designed and validated as novel GSMs. Compound 11 and azepine 20 exhibit robust lowering of CSF Aß42 in rats treated with a 30 mg/kg oral dose.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid Precursor Protein Secretases/metabolism , Alkenes/chemistry , Alkenes/pharmacology , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/cerebrospinal fluid , Animals , Binding Sites/physiology , HEK293 Cells , Humans , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/cerebrospinal fluid , Rats , Structure-Activity RelationshipABSTRACT
A series of potent and orally bioavailable 3,4-diaminocyclobutenediones with various fluoroalkyl groups as alpha side chain were prepared and found to show significant improvements in the binding affinities towards both CXCR2 and CXCR1 receptors.
Subject(s)
Cyclobutanes/chemical synthesis , Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Administration, Oral , Animals , Binding Sites , Cyclobutanes/administration & dosage , Cyclobutanes/metabolism , Protein Binding , Rats , Receptors, Interleukin-8A/metabolism , Receptors, Interleukin-8B/metabolismABSTRACT
A series of spiro-piperidine azetidinone were synthesized and evaluated as potential TRPV1 antagonists. An important issue of plasma stability was investigated and resolved. Further focused SAR study lead to the discovery of a potent antagonist with good oral pharmacokinetic profile in rat.
Subject(s)
Azetidines/chemical synthesis , Azetidines/pharmacokinetics , Chemistry, Pharmaceutical/methods , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , TRPV Cation Channels/antagonists & inhibitors , Administration, Oral , Animals , Drug Design , Hydrogen-Ion Concentration , Inhibitory Concentration 50 , Models, Chemical , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of potent and orally bioavailable 3,4-diaminocyclobutenediones with various amide modifications and substitution on the left side phenyl ring were prepared and found to show significant inhibitory activities towards both CXCR2 and CXCR1 receptors.
Subject(s)
Amides/chemistry , Cyclobutanes/chemical synthesis , Diamines/chemical synthesis , Phenol/chemistry , Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Administration, Oral , Animals , Area Under Curve , Chemistry, Pharmaceutical/methods , Cyclobutanes/pharmacology , Diamines/pharmacology , Drug Design , Humans , Inflammation , Kinetics , Models, Chemical , Rats , Structure-Activity RelationshipABSTRACT
A series of 3,4- and 3,5-disubstituted phenyl-containing cyclobutenedione analogues were synthesized and evaluated as CXCR2 receptor antagonists. Variations in the disubstitution pattern of the phenyl ring afforded new compounds with potent CXCR2 binding affinity in the low nanomolar ranges. Moreover, two potent compounds 19 and 26 exhibited good oral pharmacokinetic profiles.
Subject(s)
Cyclobutanes/chemical synthesis , Cyclobutanes/pharmacology , Receptors, Interleukin-8B/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Cyclobutanes/chemistry , Haplorhini , Molecular Structure , Protein Binding , Rats , Structure-Activity RelationshipABSTRACT
A series of novel and potent 3,4-diamino-2,5-thiadiazole-1-oxides were prepared and found to show excellent binding affinities for CXCR2 and CXCR1 receptors and excellent inhibitory activity of Gro-alpha and IL-8 mediated in vitro hPMN MPO release of CXCR2 and CXCR1 expressing cell lines. On the other hand, a closely related 3,4-diamino-2,5-thiadiazole-dioxide did not show functional activity despite its excellent binding affinities for CXCR2 and CXCR1 in membrane binding assays. A detailed SAR has been discussed in these two closely related structures.
Subject(s)
Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Animals , Chemokine CXCL1/chemistry , Chemokine CXCL1/pharmacology , Chemotactic Factors/chemistry , Chemotactic Factors/pharmacology , Humans , Interleukin-8/chemistry , Interleukin-8/pharmacology , Kinetics , Neutrophils/drug effects , Neutrophils/enzymology , Oxides/chemical synthesis , Oxides/chemistry , Oxides/pharmacokinetics , Oxides/pharmacology , Peroxidase/metabolism , Rats , Structure-Activity Relationship , Thiadiazoles/chemical synthesis , Thiadiazoles/chemistry , Thiadiazoles/pharmacokinetics , Thiadiazoles/pharmacologyABSTRACT
Comprehensive SAR studies were undertaken in the 3,4-diaminocyclobut-3-ene-1,2-dione class of CXCR2/CXCR1 receptor antagonists to explore the role of the heterocycle on chemokine receptor binding affinities, functional activity, as well as oral exposure in rat. The nature of the heterocycle as well as the requisite substitution pattern around the heterocycle was shown to have a dramatic effect on the overall biological profile of this class of compounds. The furyl class, particularly the 4-halo adducts, was found to possess superior binding affinities for both the CXCR2 and CXCR1 receptors, functional activity, as well as oral exposure in rat versus other heterocyclic derivatives.
Subject(s)
Cyclobutanes/chemistry , Cyclobutanes/pharmacology , Diamines/chemistry , Diamines/pharmacology , Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Animals , Cell Line , Cyclobutanes/chemical synthesis , Diamines/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Mice , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Herein we describe structure-activity relationship (SAR) and metabolite identification (Met-ID) studies that provided insight into the origin of time-dependent inhibition (TDI) of cytochrome P450 3A4 (CYP3A4) by compound 1. Collectively, these efforts revealed that bioactivation of the fluoropyrimidine moiety of 1 led to reactive metabolite formation via oxidative defluorination and was responsible for the observed TDI. We discovered that substitution at both the 4- and 6-positions of the 5-fluoropyrimidine of 1 was necessary to ameliorate this TDI as exemplified by compound 19.
Subject(s)
Cytochrome P-450 CYP3A Inhibitors/chemistry , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Cytochrome P-450 CYP3A/metabolism , Pyrimidines/chemistry , Pyrimidines/pharmacology , Animals , Cytochrome P-450 CYP3A Inhibitors/pharmacokinetics , Humans , Kinetics , Pyrimidines/pharmacokinetics , Rats , Structure-Activity Relationship , Tissue DistributionABSTRACT
A novel series of tricyclic tetrahydroquinolines were identified as potent and selective CRTh2 receptor antagonists. The agonism and antagonism switch was achieved through structure-based drug design (SBDD) using a CRTh2 receptor homologue model. The challenge of very low exposures in pharmacokinetic studies was overcome by exhaustive medicinal chemistry lead optimization through focused SAR studies on the tricyclic core. Further optimization resulted in the identification of the preclinical candidate 4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic acid (15c, MK-8318) with potent and selective CRTh2 antagonist activity and a favorable PK profile suitable for once daily oral dosing for potential treatment of asthma.
ABSTRACT
We describe our optimization efforts to improve the physicochemical properties, solubility, and off-target profile of 1, an inhibitor of TarO, an early stage enzyme in the biosynthetic pathway for wall teichoic acid (WTA) synthesis. Compound 1 displayed a TarO IC50 of 125 nM in an enzyme assay and possessed very high lipophilicity (clogP = 7.1) with no measurable solubility in PBS buffer. Structure-activity relationship (SAR) studies resulted in a series of compounds with improved lipophilic ligand efficiency (LLE) consistent with the reduction of clogP. From these efforts, analog 9 was selected for our initial in vivo study, which in combination with subefficacious dose of imipenem (IPM) robustly lowered the bacterial burden in a neutropenic Staphylococci murine infection model. Concurrent with our in vivo optimization effort using 9, we further improved LLE as exemplified by a much more druglike analog 26.
Subject(s)
Lipids/chemistry , Small Molecule Libraries , Animals , Female , Methicillin-Resistant Staphylococcus aureus/drug effects , Methicillin-Resistant Staphylococcus aureus/growth & development , Mice , Mice, Inbred BALB C , Microbial Sensitivity Tests , Solubility , Structure-Activity RelationshipABSTRACT
Structure-activity studies on lead cyclobutenedione 3 led to the discovery of 4 (SCH 527123), a potent, orally bioavailable CXCR2/CXCR1 receptor antagonist with excellent cell-based activity. Compound 4 displayed good oral bioavailability in rat and may be a potential therapeutic agent for the treatment of various inflammatory diseases.