ABSTRACT
The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na(+) regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na(+) homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na(+) homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes.
Subject(s)
Amides/pharmacology , Antimalarials/pharmacology , Benzimidazoles/pharmacology , Erythrocytes/parasitology , Malaria/parasitology , Plasmodium falciparum/drug effects , Pyrazoles/pharmacology , Sodium/metabolism , Adenosine Triphosphatases/genetics , Adenosine Triphosphatases/metabolism , Female , Homeostasis/drug effects , Humans , Male , Plasmodium berghei/drug effects , Plasmodium berghei/genetics , Plasmodium berghei/metabolism , Plasmodium falciparum/enzymology , Plasmodium falciparum/genetics , Plasmodium falciparum/metabolism , Protein Kinases/genetics , Protein Kinases/metabolism , Protozoan ProteinsABSTRACT
We report herein the identification of MK-4409, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor. Starting from a high throughput screening (HTS) hit, medicinal chemistry efforts focused on optimizing of FAAH inhibition in vitro potency, improving the pharmacokinetic (PK) profile, and increasing in vivo efficacy in rodent inflammatory and neuropathic pain assays.
ABSTRACT
The discovery of 1,3,8-triazaspiro[4.5]decane-2,4-diones (spirohydantoins) as a structural class of pan-inhibitors of the prolyl hydroxylase (PHD) family of enzymes for the treatment of anemia is described. The initial hit class, spirooxindoles, was identified through affinity selection mass spectrometry (AS-MS) and optimized for PHD2 inhibition and optimal PK/PD profile (short-acting PHDi inhibitors). 1,3,8-Triazaspiro[4.5]decane-2,4-diones (spirohydantoins) were optimized as an advanced lead class derived from the original spiroindole hit. A new set of general conditions for C-N coupling, developed using a high-throughput experimentation (HTE) technique, enabled a full SAR analysis of the spirohydantoins. This rapid and directed SAR exploration has resulted in the first reported examples of hydantoin derivatives with good PK in preclinical species. Potassium channel off-target activity (hERG) was successfully eliminated through the systematic introduction of acidic functionality to the molecular structure. Undesired upregulation of alanine aminotransferese (ALT) liver enzymes was mitigated and a robust on-/off-target margin was achieved. Spirohydantoins represent a class of highly efficacious, short-acting PHD1-3 inhibitors causing a robust erythropoietin (EPO) upregulation in vivo in multiple preclinical species. This profile deems spirohydantoins as attractive short-acting PHDi inhibitors with the potential for treatment of anemia.
Subject(s)
Anemia/drug therapy , Aza Compounds/chemical synthesis , Hydantoins/chemical synthesis , Hypoxia-Inducible Factor 1/metabolism , Procollagen-Proline Dioxygenase/antagonists & inhibitors , Spiro Compounds/chemical synthesis , Animals , Aza Compounds/pharmacokinetics , Aza Compounds/pharmacology , Dogs , ERG1 Potassium Channel , Erythropoietin/biosynthesis , Ether-A-Go-Go Potassium Channels/metabolism , High-Throughput Screening Assays , Humans , Hydantoins/pharmacokinetics , Hydantoins/pharmacology , Hypoxia-Inducible Factor-Proline Dioxygenases , Indoles/chemical synthesis , Indoles/pharmacokinetics , Indoles/pharmacology , Liver/drug effects , Liver/enzymology , Macaca mulatta , Mass Spectrometry , Mice , Mice, Inbred C57BL , Protein Binding , Rats , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Structure-Activity Relationship , Up-RegulationABSTRACT
We report the discovery of piperazine urea based compound 1, a potent, selective, orally bioavailable melanocortin subtype-4 receptor partial agonist. Compound 1 shows anti-obesity efficacy without potentiating erectile activity in the rodent models.
Subject(s)
Piperazines/chemistry , Receptor, Melanocortin, Type 4/agonists , Urea/analogs & derivatives , Administration, Oral , Animals , Biological Availability , Disease Models, Animal , Dogs , Drug Evaluation, Preclinical , Eating/drug effects , Haplorhini , Mice , Obesity/drug therapy , Piperazines/pharmacokinetics , Piperazines/therapeutic use , Rats , Rats, Sprague-Dawley , Receptor, Melanocortin, Type 4/genetics , Receptor, Melanocortin, Type 4/metabolism , Structure-Activity Relationship , Urea/chemistry , Urea/pharmacokinetics , Urea/therapeutic useABSTRACT
We report the development and characterization of compound 22 (MK-5046), a potent, selective small molecule agonist of BRS-3 (bombesin receptor subtype-3). In pharmacological testing using diet-induced obese mice, compound 22 caused mechanism-based, dose-dependent reductions in food intake and body weight.
ABSTRACT
We report herein the discovery of benzodiazepine sulfonamide-based bombesin receptor subtype 3 (BRS-3) agonists and their unusual chirality. Starting from a high-throughput screening lead, we prepared a series of BRS-3 agonists with improved potency and pharmacokinetic properties, of which compound 8a caused mechanism-based, dose-dependent food intake reduction and body weight loss after oral dosing in diet-induced obese mice. This effort also led to the discovery of a novel family of chiral molecules originated from the conformationally constrained seven-membered diazepine ring.
ABSTRACT
We report an SAR study of MC4R analogs containing spiroindane heterocyclic privileged structures. Compound 26 with N-Me-1,2,4-triazole moiety possesses exceptional potency at MC4R and potent anti-obesity efficacy in a mouse model. However, the efficacy is not completely mediated through MC4R. Additional SAR studies led to the discovery of compound 32, which is more potent at MC4R. Compound 32 demonstrates MC4R mediated anti-obesity efficacy in rodent models.
Subject(s)
Obesity/drug therapy , Receptor, Melanocortin, Type 4/agonists , Triazoles/pharmacology , Animals , Chromatography, High Pressure Liquid , Disease Models, Animal , Mice , Mice, Knockout , Molecular Structure , Rats , Receptor, Melanocortin, Type 4/genetics , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/therapeutic useABSTRACT
Design, syntheses and structure-activity relationships of N-acetylated piperazine privileged structures containing MC4R agonist compounds were described. The most potent derivatives were low nM MC4R selective full agonists. Several compounds from the series had modest pharmacokinetic properties.
Subject(s)
Ligands , Receptor, Melanocortin, Type 4/agonists , Animals , Humans , Piperazine , Piperazines/chemical synthesis , Piperazines/chemistry , Piperazines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptor, Melanocortin, Type 4/metabolism , Structure-Activity RelationshipABSTRACT
Design, synthesis, and SAR of a series of 3H-spiro[isobenzofuran-1,4'-piperidine] based compounds as potent, selective and orally bioavailable melanocortin subtype-4 receptor (MC4R) agonists are disclosed.
Subject(s)
Piperidines/chemistry , Receptor, Melanocortin, Type 4/agonists , Administration, Oral , Animals , Brain/metabolism , Crystallography, X-Ray , Drug Evaluation, Preclinical , Humans , Molecular Conformation , Piperidines/chemical synthesis , Piperidines/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Melanocortin, Type 4/metabolism , Spiro Compounds/chemistry , Structure-Activity RelationshipABSTRACT
We report a series of potent and selective MC4R agonists based on spiroindane amide privileged structures for potential treatments of obesity. Among the synthetic methods used, Method C allows rapid synthesis of the analogs. The series of compounds can afford high potency on MC4R as well as good rodent pharmacokinetic profiles. Compound 1r (MK-0489) demonstrates MC4R mediated reduction of food intake and body weight in mouse models. Compound 1r is efficacious in 14-day diet-induced obese (DIO) rat models.
Subject(s)
Amides/chemistry , Anti-Obesity Agents/chemistry , Obesity/drug therapy , Pyrrolidines/chemistry , Receptor, Melanocortin, Type 4/agonists , Spiro Compounds/chemistry , Amides/pharmacokinetics , Amides/therapeutic use , Animals , Anti-Obesity Agents/pharmacokinetics , Anti-Obesity Agents/therapeutic use , Body Weight/drug effects , Humans , Mice , Mice, Knockout , Pyrrolidines/pharmacokinetics , Pyrrolidines/therapeutic use , Rats , Rats, Sprague-Dawley , Receptor, Melanocortin, Type 4/metabolism , Spiro Compounds/pharmacokinetics , Spiro Compounds/therapeutic use , Structure-Activity RelationshipABSTRACT
We report the design, synthesis and properties of spiroindane based compound 1, a potent, selective, orally bioavailable, non-peptide melanocortin subtype-4 receptor agonist. Compound 1 shows excellent erectogenic activity in the rodent models.
Subject(s)
Erectile Dysfunction/drug therapy , Indans/chemistry , Indans/therapeutic use , Receptor, Melanocortin, Type 4/agonists , Receptor, Melanocortin, Type 4/metabolism , Spiro Compounds/chemistry , Spiro Compounds/therapeutic use , Animals , CHO Cells , Cricetinae , Cricetulus , Dogs , Haplorhini , Humans , Indans/pharmacokinetics , Indans/pharmacology , Male , Mice , Molecular Structure , Protein Binding , Rats , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
This Letter describes a series of potent and selective BRS-3 agonists containing a biarylethylimidazole pharmacophore. Extensive SAR studies were carried out with different aryl substitutions. This work led to the identification of a compound 2-{2-[4-(pyridin-2-yl)phenyl]ethyl}-5-(2,2-dimethylbutyl)-1H-imidazole 9 with excellent binding affinity (IC(50)=18 nM, hBRS-3) and functional agonist activity (EC(50)=47 nM, 99% activation). After oral administration, compound 9 had sufficient exposure in diet induced obese mice to demonstrate efficacy in lowering food intake and body weight via BRS-3 activation.
Subject(s)
Imidazoles/chemistry , Imidazoles/therapeutic use , Obesity/drug therapy , Receptors, Bombesin/agonists , Receptors, Bombesin/metabolism , Animals , Body Weight/drug effects , Eating/drug effects , Humans , Imidazoles/pharmacokinetics , Mice , Rats , Structure-Activity RelationshipABSTRACT
We report SAR studies on a novel non-peptidic bombesin receptor subtype-3 (BRS-3) agonist lead series derived from high-throughput screening hit RY-337. This effort led to the discovery of compound 22e with significantly improved potency at both rodent and human BRS-3.
Subject(s)
Drug Discovery , Imidazoles/chemistry , Imidazoles/pharmacology , Receptors, Bombesin/agonists , Animals , Biological Availability , Humans , Imidazoles/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
Nodulisporic acid A (1) is a structurally complex fungal metabolite that exhibits systemic efficacy against fleas via modulation of an invertebrate specific glutamate-gated ion channel. In order to identify a nodulisporamide suitable for monthly oral dosing in dogs, a library of 335 nodulisporamides was examined in an artificial flea feeding system for intrinsic systemic potency as well as in a mouse/bedbug assay for systemic efficacy and safety. A cohort of 66 nodulisporamides were selected for evaluation in a dog/flea model; pharmacokinetic analysis correlated plasma levels with flea efficacy. These efforts resulted in the identification of the development candidate N-tert-butyl nodulisporamide (3) as a potent and efficacious once monthly oral agent for the control of fleas and ticks on dogs and cats which was directly compared to the topical agents fipronil and imidacloprid, with favorable results obtained. Multidose studies over 3 months confirmed the in vivo ectoparasiticidal efficacy and established that 3 lacked overt mammalian toxicity. Tissue distribution studies in mice using [(14)C]-labeled 3 indicate that adipose beds serve as ligand depots, contributing to the long terminal half-lives of these compounds.
Subject(s)
Insect Control , Insecticides , Siphonaptera , Ticks , Adipose Tissue/metabolism , Administration, Oral , Animals , Cats , Dogs , Female , Indole Alkaloids/chemical synthesis , Indole Alkaloids/pharmacokinetics , Indole Alkaloids/pharmacology , Indoles , Insecticides/administration & dosage , Insecticides/chemical synthesis , Male , Mice , Tissue DistributionABSTRACT
Novel 2,3-diarylindoles bearing an amine substituent at the indole 5- and 6-positions have been synthesized and evaluated as anticoccidial agents in both in vitro and in vivo assays. Both subnanomolar in vitro activity and broad spectrum in vivo potency were detected for several compounds, particularly compound 27.
Subject(s)
Coccidiostats/chemical synthesis , Indoles/chemical synthesis , Animals , Coccidiosis/drug therapy , Coccidiosis/enzymology , Coccidiosis/parasitology , Coccidiostats/pharmacology , Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors , Eimeria tenella/drug effects , Eimeria tenella/enzymology , Eimeria tenella/growth & development , Indoles/pharmacology , Poultry/parasitology , Pyridines/chemical synthesisABSTRACT
Novel 5,6-diarylimidazo[2,1-b][1,3]thiazoles bearing an amine substituent at the imidazothiazole 2-position have been synthesized and evaluated as anticoccidial agents in both in vitro and in vivo assays. Both subnanomolar in vitro activity and broad spectrum in vivo potency were detected for several compounds, particularly compound 10.
Subject(s)
Coccidiostats/chemical synthesis , Coccidiostats/pharmacology , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Animals , Coccidiostats/chemistry , Combinatorial Chemistry Techniques , Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors , Eimeria/drug effects , Imidazoles/chemistry , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Thiazoles/chemistryABSTRACT
Discovery of a series of tert-butyl pyrrolidine derived, potent and orally bioavailable melanocortin receptor subtype-4 (MC4R) selective modulators is disclosed.
Subject(s)
Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacokinetics , Receptor, Melanocortin, Type 4/agonists , Administration, Oral , Humans , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , TelomeraseABSTRACT
A series of 3-amino-1,5-benzodiazepinones were synthesized and evaluated as potential sodium channel blockers in a functional, membrane potential-based assay. One member of this series displayed subnanomolar, state-dependent sodium channel block, and was orally efficacious in a mouse model of epilepsy.