ABSTRACT
Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. Toxicology studies in rats indicate a > 30-fold safety margin in relation to the predicted human efficacious exposure. In conclusion, MMV693183 represents a promising candidate for further (pre)clinical development with a novel mode of action for treatment of malaria and blocking transmission.
Subject(s)
Antimalarials , Folic Acid Antagonists , Malaria, Falciparum , Malaria, Vivax , Malaria , Animals , Antimalarials/pharmacology , Antimalarials/therapeutic use , Malaria/drug therapy , Malaria, Falciparum/drug therapy , Malaria, Vivax/drug therapy , Mice , Pantothenic Acid/analogs & derivatives , Plasmodium falciparum/genetics , RatsABSTRACT
Antagonism of the chemokine receptor CXCR2 has been proposed as a strategy for the treatment of inflammatory diseases such as arthritis, chronic obstructive pulmonary disease and asthma. Earlier series of bicyclic CXCR2 antagonists discovered at AstraZeneca were shown to have low solubility and poor oral bioavailability. In this Letter we describe the design, synthesis and characterisation of a new series of monocyclic CXCR2 antagonists with improved solubility and good pharmacokinetic profiles.
Subject(s)
Amides/pharmacology , Drug Discovery , Pyrimidines/pharmacology , Receptors, Interleukin-8B/antagonists & inhibitors , Amides/chemical synthesis , Amides/chemistry , Animals , Biological Availability , Dose-Response Relationship, Drug , Humans , Molecular Conformation , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Solubility , Structure-Activity RelationshipABSTRACT
Starting from adenosine triphosphate (ATP), the identification of a novel series of P2Y(12) receptor antagonists and exploitation of their SAR is described. Modifications of the acidic side chain and the purine core and investigation of hydrophobic substituents led to a series of neutral molecules. The leading compound, 17 (AZD6140), is currently in a large phase III clinical trial for the treatment of acute coronary syndromes and prevention of thromboembolic clinical sequelae.
Subject(s)
Adenosine Triphosphate/therapeutic use , Adenosine/analogs & derivatives , Membrane Proteins/antagonists & inhibitors , Purinergic P2 Receptor Antagonists , Thrombosis/prevention & control , Adenosine/therapeutic use , Administration, Oral , Animals , Humans , Receptors, Purinergic P2Y12 , TicagrelorABSTRACT
Starting with the weak agonist indomethacin, a series of potent, selective CRTh2 (DP(2)) antagonists have been discovered as potential treatments for asthma, allergic rhinitis and other inflammatory diseases.
Subject(s)
Asthma/drug therapy , Indomethacin/pharmacology , Inflammation/drug therapy , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Rhinitis/drug therapy , Chemistry, Pharmaceutical , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Protein Binding , Receptors, Prostaglandin/metabolismABSTRACT
A simple and high-yielding method for the preparation of cyclopropane amino acids is described. The novel method involves the one-pot cyclopropanation of readily available dehydroamino acids using aryl and unsaturated diazo compounds generated in situ from the corresponding tosylhydrazone salts. It was found that thermal 1,3-dipolar cycloaddition followed by nitrogen extrusion gave the cyclopropane amino acid derivatives with good E selectivity, while reactions in the presence of meso-tetraphenylporphyrin iron chloride gave predominantly the corresponding Z isomers. The synthetic utility of this process was demonstrated in the synthesis of (+/-)-(Z)-2,3-methanophenylalanine [(+/-)-(Z)-1], the anti-Parkinson (+/-)-(E)-2,3-methano-m-tyrosine [(+/-)-(E)-2], and the natural product (+/-)-coronamic acid [(+/-)-3].
Subject(s)
Amino Acids/chemical synthesis , Cyclopropanes/chemical synthesis , Diazonium Compounds/chemistry , Amino Acids/chemistry , Cyclopropanes/chemistry , Models, Chemical , Molecular Structure , StereoisomerismABSTRACT
This paper describes the development of a QSAR model for the rational control of functional duration of topical long-acting dual D(2)-receptor/beta(2)-adrenoceptor agonists for the treatment of chronic obstructive pulmonary disease. A QSAR model highlighted the importance of lipophilicity and ionization in controlling beta(2) duration. It was found that design rules logD(7.4) > 2, secondary amine pK(a) > 8.0, yielded ultra-long duration compounds. This model was used successfully to guide the design of long- and ultra-long-acting compounds. The QSAR model is discussed in terms of the exosite model, and the plasmalemma diffusion microkinetic hypothesis, for the control of beta(2) duration. Data presented strongly suggests that beta(2) duration is primarily controlled by the membrane affinity of these compounds.
Subject(s)
Adrenergic beta-Agonists/chemistry , Albuterol/analogs & derivatives , Dopamine Agonists/chemistry , Quantitative Structure-Activity Relationship , Receptors, Adrenergic, beta-2/drug effects , Adrenergic beta-Agonists/chemical synthesis , Adrenergic beta-Agonists/pharmacology , Albuterol/pharmacokinetics , Algorithms , Animals , Biological Transport , Dopamine Agonists/chemical synthesis , Dopamine Agonists/pharmacology , Drug Design , Guinea Pigs , In Vitro Techniques , Kinetics , Models, Molecular , Muscle Relaxation/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Salmeterol Xinafoate , Trachea/drug effects , Trachea/metabolism , Trachea/physiologyABSTRACT
A convenient one-pot procedure for the preparation of pyrazoles by 1,3-dipolar cycloaddition of diazo compounds generated in situ has been developed. Diazo compounds derived from aldehydes were reacted with terminal alkynes to furnish regioselectively 3,5-disubstituted pyrazoles. Furthermore, the reaction of N-vinylimidazole and diazo compounds derived from aldehydes gave exclusively 3-substituted pyrazoles in a one-pot process.
ABSTRACT
The metabolism of 3-([3-(2-Chlorophenyl)-4,5-dihydro-5-thioxo-1H-1,2,4-triazol-1-yl]methyl)benzonitrile (AR-C133611XX) was studied in isolated dog hepatocytes. The major metabolite of AR-C133611XX was characterized by high performance liquid chromatography-mass spectrometry and NMR and found to be the product of direct glucuronidation. Evidence from 1H and 13C-NMR chemical shifts and a long-range proton carbon correlation experiment was used to deduce that glucuronidation had taken place on the sulfur atom. Full NMR data on this unusual metabolite is presented. Substitution or replacement of the sulfur atom resulted in a significant decrease in the observed rate of glucuronidation.