ABSTRACT
Cyclophilins are a family of peptidyl-prolyl isomerases that are implicated in a wide range of diseases including hepatitis C. Our aim was to discover through total synthesis an orally bioavailable, non-immunosuppressive cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus (HCV) activity that could serve as part of an all oral antiviral combination therapy. An initial lead 2 derived from the sanglifehrin A macrocycle was optimized using structure based design to produce a potent and orally bioavailable inhibitor 3. The macrocycle ring size was reduced by one atom, and an internal hydrogen bond drove improved permeability and drug-like properties. 3 demonstrates potent Cyp inhibition ( Kd = 5 nM), potent anti-HCV 2a activity (EC50 = 98 nM), and high oral bioavailability in rat (100%) and dog (55%). The synthetic accessibility and properties of 3 support its potential as an anti-HCV agent and for interrogating the role of Cyp inhibition in a variety of diseases.
Subject(s)
Cyclophilins/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/pharmacokinetics , Administration, Oral , Antiviral Agents/administration & dosage , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Biological Availability , Cell Line , Cyclophilins/chemistry , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Hepacivirus/drug effects , Lactones/administration & dosage , Lactones/chemistry , Lactones/pharmacokinetics , Lactones/pharmacology , Models, Molecular , Protein Conformation , Spiro Compounds/administration & dosage , Spiro Compounds/chemistry , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacologyABSTRACT
Cyclophilin inhibition has been a target for the treatment of hepatitis C and other diseases, but the generation of potent, drug-like molecules through chemical synthesis has been challenging. In this study, a set of macrocyclic cyclophilin inhibitors was synthesized based on the core structure of the natural product sanglifehrin A. Initial compound optimization identified the valine-m-tyrosine-piperazic acid tripeptide (Val-m-Tyr-Pip) in the sanglifehrin core, stereocenters at C14 and C15, and the hydroxyl group of the m-tyrosine (m-Tyr) residue as key contributors to compound potency. Replacing the C18-C21 diene unit of sanglifehrin with a styryl group led to potent compounds that displayed a novel binding mode in which the styrene moiety engaged in a π-stacking interaction with Arg55 of cyclophilin A (Cyp A), and the m-Tyr residue was displaced into solvent. This observation allowed further simplifications of the scaffold to generate new lead compounds in the search for orally bioavailable cyclophilin inhibitors.
Subject(s)
Cyclophilins/antagonists & inhibitors , Cells, Cultured , Chromatography, Liquid , Crystallography, X-Ray , Drug Discovery , Humans , Hydrogen Bonding , Lactones/chemistry , Lactones/pharmacology , Proton Magnetic Resonance Spectroscopy , Spectrometry, Mass, Electrospray Ionization , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity Relationship , Surface Plasmon Resonance , ThermodynamicsABSTRACT
This Letter describes the discovery of GSK189254 and GSK239512 that were progressed as clinical candidates to explore the potential of H3 receptor antagonists as novel therapies for the treatment of Alzheimer's disease and other dementias. By carefully controlling the physicochemical properties of the benzazepine series and through the implementation of an aggressive and innovative screening strategy that employed high throughput in vivo assays to efficiently triage compounds, the medicinal chemistry effort was able to rapidly progress the benzazepine class of H3 antagonists through to the identification of clinical candidates with robust in vivo efficacy and excellent developability properties.
Subject(s)
Benzazepines/chemistry , Histamine H3 Antagonists/chemistry , Receptors, Histamine H3/chemistry , Animals , Benzazepines/pharmacokinetics , Dogs , Half-Life , Haplorhini , Histamine H3 Antagonists/chemical synthesis , Histamine H3 Antagonists/pharmacokinetics , Humans , Male , Microsomes, Liver/metabolism , Niacinamide/analogs & derivatives , Niacinamide/chemistry , Niacinamide/pharmacokinetics , Protein Binding , Rats , Rats, Sprague-Dawley , Receptors, Histamine H3/metabolism , Structure-Activity RelationshipABSTRACT
This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing an H3 driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties.
Subject(s)
Benzazepines/chemistry , Histamine H3 Antagonists/chemistry , Receptors, Histamine H3/chemistry , Animals , Benzazepines/chemical synthesis , Benzazepines/pharmacokinetics , Cytochrome P-450 CYP2D6/chemistry , Cytochrome P-450 CYP2D6/metabolism , Drug Evaluation, Preclinical , Half-Life , Histamine H3 Antagonists/chemical synthesis , Histamine H3 Antagonists/pharmacokinetics , Humans , Microsomes, Liver/metabolism , Protein Binding , Rats , Receptors, Histamine H3/genetics , Receptors, Histamine H3/metabolism , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Structure-Activity RelationshipABSTRACT
A backup molecule to compound 2 was sought by targeting the most likely metabolically vulnerable site in this molecule. Compound 18 was subsequently identified as a potent P2X(7) antagonist with very low in vivo clearance and high oral bioavailability in all species examined. Some evidence to support the role of P2X(7) in the etiology of pain is also presented.
Subject(s)
Imidazolines/pharmacology , Purinergic Antagonists/pharmacology , Receptors, Purinergic P2X7/drug effects , Administration, Oral , Animals , Biological Availability , Half-Life , Haplorhini , Imidazolines/administration & dosage , Imidazolines/chemistry , Imidazolines/pharmacokinetics , Purinergic Antagonists/administration & dosage , Purinergic Antagonists/chemistry , Purinergic Antagonists/pharmacokinetics , RatsABSTRACT
A computational lead-hopping exercise identified compound 4 as a structurally distinct P2X(7) receptor antagonist. Structure-activity relationships (SAR) of a series of pyroglutamic acid amide analogues of 4 were investigated and compound 31 was identified as a potent P2X(7) antagonist with excellent in vivo activity in animal models of pain, and a profile suitable for progression to clinical studies.
Subject(s)
Amides/pharmacology , Purinergic P2 Receptor Antagonists/pharmacology , Pyrrolidonecarboxylic Acid/chemistry , Receptors, Purinergic P2X7/drug effects , Amides/chemistry , Drug Discovery , Models, Molecular , Purinergic P2 Receptor Antagonists/chemistry , Structure-Activity RelationshipABSTRACT
Structure-activity relationships (SAR) of analogues of lead compound 1 were investigated and compound 16 was selected for further study in animal models of pain. Compound 16 was shown to be a potent antihyperalgesic agent in both the rat acute complete Freund's adjuvant (CFA) model of inflammatory pain [Iadarola, M. J.; Douglass, J.; Civelli, O.; Naranjo, J. R. rain Res.1988, 455, 205] and the knee joint model of chronic inflammatory pain [Wilson, A. W.; Medhurst, S. J.; Dixon, C. I.; Bontoft, N. C.; Winyard, L. A.; Brackenborough, K. T.; De Alba, J.; Clarke, C. J.; Gunthorpe, M. J.; Hicks, G. A.; Bountra, C.; McQueen, D. S.; Chessell, I. P. Eur. J. Pain2006, 10, 537].
Subject(s)
Acetamides/chemistry , Purinergic P2X Receptor Antagonists , Pyrazoles/chemistry , Acetamides/chemical synthesis , Acetamides/therapeutic use , Administration, Oral , Animals , Disease Models, Animal , Humans , Pain/drug therapy , Pyrazoles/chemical synthesis , Rats , Receptors, Purinergic P2X7/metabolism , Structure-Activity RelationshipABSTRACT
BACKGROUND AND PURPOSE: AZ11645373 and N-{2-methyl-5-[(1R, 5S)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-ylcarbonyl]phenyl}-2-tricyclo[3.3.1.13,7]dec-1-ylacetamide hydrochloride (compound-22) are recently described P2X(7) receptor antagonists. In this study we have further characterized these compounds to determine their mechanism of action and interaction with other species orthologues. EXPERIMENTAL APPROACH: Antagonist effects at recombinant and chimeric P2X(7) receptors were assessed by ethidium accumulation and radioligand-binding studies. KEY RESULTS: AZ11645373 and compound-22 were confirmed as selective non-competitive antagonists of human or rat P2X(7) receptors respectively. Both compounds were weak antagonists of the mouse and guinea-pig P2X(7) receptors and, for each compound, their potency estimates at human and dog P2X(7) receptors were similar. The potency of compound-22 was moderately temperature-dependent while that of AZ11645373 was not. The antagonist effects of both compounds were slowly reversible and were not prevented by decavanadate, suggesting that they were allosteric antagonists. Indeed, the compounds competed for binding sites labelled by an allosteric radio-labelled P2X(7) receptor antagonist. The species selectivity of AZ11645373, but not compound-22, was influenced by the nature of the amino acid at position 95 of the P2X(7) receptor. N(2)-(3,4-difluorophenyl)-N(1)-[2-methyl-5-(1-piperazinylmethyl)phenyl]glycinamide dihydrochloride, a positive allosteric modulator of the rat receptor, reduced the potency of compound-22 at the rat receptor but had little effect on the actions of AZ11645373. CONCLUSIONS: AZ11645373 and compound-22 are allosteric antagonists of human and rat P2X(7) receptors respectively. The differential interaction of the two compounds with the receptor suggests there may be more than one allosteric regulatory site on the P2X(7) receptor at which antagonists can bind and affect receptor function.
Subject(s)
Adamantane/analogs & derivatives , Azabicyclo Compounds/pharmacology , Purinergic P2 Receptor Antagonists , Thiazoles/pharmacology , Adamantane/metabolism , Adamantane/pharmacology , Adenosine Triphosphate/analogs & derivatives , Adenosine Triphosphate/metabolism , Adenosine Triphosphate/pharmacology , Animals , Azabicyclo Compounds/metabolism , Binding Sites , Cell Line, Tumor , Dogs , Dose-Response Relationship, Drug , Glycine/analogs & derivatives , Glycine/pharmacology , Guinea Pigs , Humans , Mice , Piperazines/pharmacology , Protein Conformation , Radioligand Assay , Rats , Receptors, Purinergic P2/chemistry , Receptors, Purinergic P2/genetics , Receptors, Purinergic P2/metabolism , Receptors, Purinergic P2X7 , Recombinant Fusion Proteins/antagonists & inhibitors , Recombinant Proteins/antagonists & inhibitors , Species Specificity , Structure-Activity Relationship , Temperature , Thiazoles/metabolism , Transduction, Genetic , Vanadates/pharmacologyABSTRACT
As part of an on-going lead optimisation effort, a cross screening exercise identified an aryl sulphonyl amide hit that was optimised to afford a highly potent series of ghrelin receptor agonists.
Subject(s)
Chemistry, Pharmaceutical/methods , Ghrelin/chemistry , Receptors, Ghrelin/antagonists & inhibitors , Sulfones/chemistry , Administration, Oral , Animals , Biological Availability , Drug Design , Growth Hormone/chemistry , Male , Models, Chemical , Protein Processing, Post-Translational , Rats , Rats, Sprague-Dawley , Receptors, Ghrelin/chemistry , Structure-Activity RelationshipABSTRACT
Modification of the potent imidazole-based B-Raf inhibitor SB-590885 resulted in the identification of a series of furan-based derivatives with enhanced CNS penetration. One such compound, SB-699393 (17), was examined in vivo to challenge the hypothesis that selective B-Raf inhibitors may be of value in the treatment of stroke.
Subject(s)
Central Nervous System/drug effects , Furans/chemical synthesis , Furans/pharmacology , Indans/chemical synthesis , Indans/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Animals , Furans/chemistry , Imidazoles/chemistry , Imidazoles/pharmacology , Indans/chemistry , Molecular Structure , Pyridines/chemistry , Pyridines/pharmacology , Rats , Stroke/drug therapy , Structure-Activity RelationshipABSTRACT
A series of small molecule orally bioavailable ghrelin receptor agonists have been identified through systematic optimisation of a high throughput screening hit.
Subject(s)
Indoles/pharmacology , Receptors, Ghrelin/agonists , Sulfonamides/pharmacology , Administration, Oral , Animals , Biological Availability , Fluorescence , Indoles/chemical synthesis , Male , Molecular Structure , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT1B/metabolism , Receptors, Ghrelin/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesisABSTRACT
High throughput screening combined with efficient datamining and parallel synthesis led to the discovery of a novel series of indolines showing potent in vitro ghrelin receptor agonist activity and acceleration of gastric emptying in rats.
Subject(s)
Indoles/chemistry , Receptors, Ghrelin/agonists , Animals , Gastric Emptying/drug effects , Gastric Emptying/physiology , Human Growth Hormone/agonists , Humans , Indoles/pharmacology , Rats , Receptors, Ghrelin/physiology , StereoisomerismABSTRACT
A novel triarylimidazole derivative, SB-590885 (33), bearing a 2,3-dihydro-1H-inden-1-one oxime substituent has been identified as a potent and extremely selective inhibitor of B-Raf kinase.
Subject(s)
Imidazoles/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Cyclization , Imidazoles/chemical synthesis , Imidazoles/chemistry , Molecular Structure , Proto-Oncogene Proteins B-raf/chemistry , Structure-Activity RelationshipABSTRACT
The novel imidazo[4,5-c]pyridine 1,2,5-oxadiazol-3-yl template affords an excellent start point for identification of inhibitors of a number of protein kinases. Here we report on its optimisation for mitogen and stress-activated protein kinase-1 (MSK-1) inhibitory activity, and selectivity over other kinases.
Subject(s)
Amines/pharmacology , Enzyme Inhibitors/pharmacology , Imidazoles/pharmacology , Oxadiazoles/pharmacology , Pyridines/pharmacology , Ribosomal Protein S6 Kinases, 90-kDa/antagonists & inhibitors , Amines/chemical synthesis , Amines/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Imidazoles/chemical synthesis , Imidazoles/chemistry , Molecular Structure , Oxadiazoles/chemical synthesis , Oxadiazoles/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
A novel series of imidazo[4,5-c]pyridines bearing a 1,2,5-oxadiazol-3-ylamine functionality has been developed. These are potent inhibitors of mitogen and stress-activated protein kinase-1.
Subject(s)
Amines/pharmacology , Enzyme Inhibitors/pharmacology , Imidazoles/pharmacology , Oxadiazoles/pharmacology , Pyridines/pharmacology , Ribosomal Protein S6 Kinases, 90-kDa/antagonists & inhibitors , Amines/chemical synthesis , Amines/classification , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/classification , Imidazoles/chemical synthesis , Imidazoles/classification , Molecular Structure , Oxadiazoles/chemical synthesis , Oxadiazoles/classification , Pyridines/chemical synthesis , Pyridines/classification , Structure-Activity RelationshipABSTRACT
A substantial acceleration of the Baylis-Hillman reaction between cyclohexenone and benzaldehyde has been observed when the reaction is conducted in water. Several different amine catalysts were tested, and as with reactions conducted in the absence of solvent, 3-hydroxyquinuclidine was found to be the optimum catalyst in terms of rate. The reaction has been extended to other aldehyde electrophiles including pivaldehyde. Attempts to extend this work to acrylates was only partially successful as rapid hydrolysis of methyl and ethyl acrylates occurred under the base-catalyzed and water-promoted conditions. However, tert-butyl acrylates were sufficiently stable to couple with relatively reactive electrophiles. Further studies on the use of polar solvents revealed that formamide also provided significant acceleration and the use of 5 equiv of formamide (optimum amount) gave faster rates than reactions conducted in water. Using formamide, further acceleration was achieved in the presence of Yb(OTf)(3) (5 mol %). The scope of the new conditions was tested with a range of Michael acceptors and benzaldehyde and with a range of electrophiles and ethyl acrylate. The origin of the rate acceleration is discussed.