ABSTRACT
A new series of glycine-derived ligands of the α(2)δ subunit of voltage gated calcium channels is described. Several novel compounds (7) based on (6) were prepared that possessed a potency <100 nM in the α(2)δ binding assay.
Subject(s)
Calcium Channels/drug effects , Glycine/chemical synthesis , Ligands , Alkylation , Glycine/chemistry , Glycine/pharmacology , Inhibitory Concentration 50 , Molecular Structure , Protein Subunits/chemistry , Structure-Activity RelationshipABSTRACT
PknB is an essential serine/threonine kinase of Mycobacterium tuberculosis with possible roles in a number of signalling pathways involved in cell division and metabolism. We screened a library of >50,000 compounds for inhibitors of the in vitro phosphorylation of GarA (Rv1827) by PknB and identified a number of inhibitors. A program of synthetic medicinal chemistry was subsequently conducted around one class of inhibitors and was successful in generating ATP competitive inhibitors with potency in the nanomolar range. Compounds in this class showed cross-reactivity with the related M. tuberculosis kinase, PknF, but not with PknG in an in vitro autophosphorylation assay. These synthesised inhibitors were able to prevent the growth of M. tuberculosis in an Alamar blue assay and in an intracellular model of infection, but only in the micromolar range. We attempted to determine if cell wall permeability was an explanation for the discrepancy between the potent in vitro compared with relatively poor in vivo activity, but found no evidence that the activity of the inhibitors could be improved by weakening the cell wall. Despite a number of drug discovery efforts attempting to develop inhibitors against PknB, it is yet to be reported that any such inhibitors prevent mycobacterial growth at submicromolar concentrations.
Subject(s)
Anti-Bacterial Agents/pharmacology , Macrophages/drug effects , Mycobacterium tuberculosis/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Tuberculosis/drug therapy , Anti-Bacterial Agents/metabolism , Cell Division , Cells, Cultured , Drug Discovery , Humans , Mycobacterium tuberculosis/growth & development , Mycobacterium tuberculosis/metabolism , Signal Transduction/drug effects , Tuberculosis/metabolismABSTRACT
A range of 3-alkylated five-membered ring derivatives of Gabapentin were synthesized and several were found to have good levels of potency against the alpha2delta calcium subunit of a voltage-gated calcium channel. Two compounds were profiled in in vivo models of pain and anxiety.
Subject(s)
Amines/chemical synthesis , Amino Acids/chemical synthesis , Anti-Anxiety Agents/chemical synthesis , Cyclohexanecarboxylic Acids/chemical synthesis , Cyclopentanes/chemical synthesis , gamma-Aminobutyric Acid/chemical synthesis , Amines/chemistry , Amines/pharmacology , Amino Acids/chemistry , Amino Acids/pharmacology , Animals , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacology , Calcium Channels/metabolism , Carrageenan/pharmacology , Cyclohexanecarboxylic Acids/chemistry , Cyclohexanecarboxylic Acids/pharmacology , Cyclopentanes/chemistry , Cyclopentanes/pharmacology , Gabapentin , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Rats , Stereoisomerism , gamma-Aminobutyric Acid/chemistry , gamma-Aminobutyric Acid/pharmacologyABSTRACT
A range of 3,4-alkylated five-membered ring derivatives of gabapentin were synthesised. One compound (21) had an excellent level of potency against alpha(2)delta and was profiled in in vivo models of pain and anxiety.
Subject(s)
Amines/chemistry , Amino Acids/chemical synthesis , Anti-Anxiety Agents/chemical synthesis , Cyclohexanecarboxylic Acids/chemistry , Cyclopentanes/chemical synthesis , gamma-Aminobutyric Acid/chemistry , Amines/chemical synthesis , Amines/pharmacokinetics , Amino Acids/chemistry , Amino Acids/pharmacology , Animals , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacokinetics , Cyclohexanecarboxylic Acids/chemical synthesis , Cyclohexanecarboxylic Acids/pharmacokinetics , Cyclopentanes/chemistry , Cyclopentanes/pharmacology , Disease Models, Animal , Gabapentin , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Rats , gamma-Aminobutyric Acid/chemical synthesis , gamma-Aminobutyric Acid/pharmacokineticsABSTRACT
Synthesis of a number of bicyclic five-membered ring derivatives of gabapentin led to the identification of two compounds, (-)-(11A) and (20A) which both had an excellent level of potency against alpha(2)delta and were profiled in an in vivo model of neuropathic pain.
Subject(s)
Amines/chemical synthesis , Amino Acids/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Cyclohexanecarboxylic Acids/chemical synthesis , gamma-Aminobutyric Acid/chemical synthesis , Amines/chemistry , Amines/pharmacokinetics , Amino Acids/chemistry , Amino Acids/pharmacokinetics , Animals , Blood-Brain Barrier/metabolism , Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/pharmacokinetics , CHO Cells , Cricetinae , Cricetulus , Cyclohexanecarboxylic Acids/chemistry , Cyclohexanecarboxylic Acids/pharmacokinetics , Gabapentin , Neuralgia/drug therapy , Pain Measurement , Rats , Stereoisomerism , Structure-Activity Relationship , gamma-Aminobutyric Acid/chemistry , gamma-Aminobutyric Acid/pharmacokineticsABSTRACT
Mycobacterium tuberculosis has an on-going impact on global public health and new therapeutics to treat tuberculosis are urgently required. The emergence of drug resistant tuberculosis poses a serious threat to the control of this pathogen, and the development of drugs that are active against the resistant strains is vital. A medium-throughput assay using the Alamar Blue reagent was set-up to identify novel inhibitors of M. tuberculosis from a library of known drugs, for which there has already been extensive research investigating their suitability and safety as human therapeutics. Of the 1514 compounds screened, 53 were demonstrated to possess inhibitory properties against M. tuberculosis at a concentration of 5microM or below. Of these, 17 were novel inhibitors while 36 were known tuberculosis drugs or had been previously described as possessing anti-tuberculosis activity. Five compounds were selected as those which represent the most promising starting points for new anti-tuberculosis agents. It was demonstrated that all five were active against intracellular M. tuberculosis in a macrophage model of infection. The anti-tuberculosis agents identified in this screen represent promising new scaffolds on which future drug development efforts can be focused.
Subject(s)
Antitubercular Agents/pharmacology , Bacterial Proteins/drug effects , Drug Design , Drug Resistance, Bacterial/drug effects , Mycobacterium tuberculosis/drug effects , Small Molecule Libraries , Tuberculosis/drug therapy , Bacterial Proteins/genetics , Drug Evaluation, Preclinical , Drug Resistance, Bacterial/genetics , Drug Resistance, Bacterial/immunology , Humans , Mycobacterium tuberculosis/genetics , Tuberculosis/genetics , Tuberculosis/immunologyABSTRACT
A series of oxadiazolone bioisosteres of pregabalin 1 and gabapentin 2 were prepared, and several were found to exhibit similar potency for the alpha(2)-delta subunit of voltage-gated calcium channels. Oxadiazolone 9 derived from 2 achieved low brain uptake but was nevertheless active in models of osteoarthritis. The high clearance associated with compound 9 was postulated to be a consequence of efflux by OAT and/or OCT, and was attenuated on co-administration with cimetidine or probenecid.
Subject(s)
Amines , Cyclohexanecarboxylic Acids , Osteoarthritis/drug therapy , Oxadiazoles/chemistry , Oxadiazoles/therapeutic use , gamma-Aminobutyric Acid/analogs & derivatives , Animals , Brain/metabolism , Drug Interactions , Drug Therapy, Combination , Gabapentin , Octamer Transcription Factors , Organic Anion Transporters , Oxadiazoles/pharmacology , Pregabalin , RatsABSTRACT
A high-throughput screening campaign identified a number of imidazopyridazines as novel inhibitors of the malarial kinase PfPK7. Further synthetic chemistry efforts enabled the preparation of a number of analogues with promising in vitro potencies. Although these compounds show likely broad spectrum inhibitory activity, they represent a useful starting point for further chemical optimisation.
Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Plasmodium falciparum/enzymology , Protozoan Proteins/antagonists & inhibitors , Pyridazines/chemical synthesis , Pyridazines/pharmacology , Animals , Antimalarials/chemistry , Combinatorial Chemistry Techniques , Drug Design , Humans , Imidazoles/chemistry , Inhibitory Concentration 50 , KB Cells , Molecular Structure , Plasmodium falciparum/drug effects , Pyridazines/chemistry , Structure-Activity RelationshipABSTRACT
The most virulent form of malaria is caused by waves of replication of blood stages of the protozoan pathogen Plasmodium falciparum. The parasite divides within an intraerythrocytic parasitophorous vacuole until rupture of the vacuole and host-cell membranes releases merozoites that invade fresh erythrocytes to repeat the cycle. Despite the importance of merozoite egress for disease progression, none of the molecular factors involved are known. We report that, just prior to egress, an essential serine protease called PfSUB1 is discharged from previously unrecognized parasite organelles (termed exonemes) into the parasitophorous vacuole space. There, PfSUB1 mediates the proteolytic maturation of at least two essential members of another enzyme family called SERA. Pharmacological blockade of PfSUB1 inhibits egress and ablates the invasive capacity of released merozoites. Our findings reveal the presence in the malarial parasitophorous vacuole of a regulated, PfSUB1-mediated proteolytic processing event required for release of viable parasites from the host erythrocyte.
Subject(s)
Erythrocytes/parasitology , Host-Parasite Interactions , Malaria/parasitology , Plasmodium falciparum/enzymology , Protozoan Proteins/physiology , Subtilisins/physiology , Animals , Antigens, Protozoan/metabolism , Antigens, Protozoan/physiology , Life Cycle Stages , Malaria/blood , Models, Biological , Plasmodium falciparum/pathogenicity , Plasmodium falciparum/ultrastructure , Protozoan Proteins/antagonists & inhibitors , Protozoan Proteins/isolation & purification , Protozoan Proteins/metabolism , Sporozoites/physiology , Subtilisins/antagonists & inhibitors , Subtilisins/isolation & purification , Subtilisins/metabolism , Vacuoles/parasitologyABSTRACT
A series of carboxylate bioisosteres of structures related to gabapentin 1 have been prepared. When the carboxylate was replaced by a tetrazole, this group was recognized by the alpha2-delta protein. Further characterization of alpha2-delta binding compounds 14a and 14b revealed a similar pattern of functional in vitro and in vivo activity to gabapentin 1.