ABSTRACT
The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis.
Subject(s)
Drug Discovery , Hydrocarbons, Fluorinated/pharmacology , Pyrimidines/pharmacology , Receptors, LHRH/antagonists & inhibitors , Animals , Caco-2 Cells , Cytochrome P-450 CYP3A Inhibitors , Drug Evaluation, Preclinical , Humans , Hydrocarbons, Fluorinated/chemistry , Hydrocarbons, Fluorinated/metabolism , Macaca fascicularis , Male , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Molecular Structure , Pyrimidines/chemistry , Pyrimidines/metabolism , Stereoisomerism , Structure-Activity Relationship , Time FactorsABSTRACT
The design synthesis and SAR of a series of chiral ring-constrained norepinephrine reuptake inhibitors with improved physicochemical properties is described. Typical compounds are potent (IC(50)s<10 nM), selective against the other monoamine transporters, weak CYP2D6 inhibitors (IC(50)s>1 microM) and stable to oxidation by human liver microsomes. In addition, the compounds exhibit a favorable polarity profile.
Subject(s)
Cytochrome P-450 CYP2D6 Inhibitors , Indans/chemical synthesis , Indans/pharmacology , Neurotransmitter Uptake Inhibitors/chemical synthesis , Neurotransmitter Uptake Inhibitors/pharmacology , Norepinephrine/antagonists & inhibitors , Atomoxetine Hydrochloride , Combinatorial Chemistry Techniques , Drug Design , Humans , Indans/chemistry , Inhibitory Concentration 50 , Microsomes, Liver/metabolism , Molecular Structure , Neurotransmitter Uptake Inhibitors/chemistry , Propylamines/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The design, synthesis, and SAR of a series of ring-constrained norepinephrine reuptake inhibitors are described. A substantially rigid inhibitor with potent functional activity at the transporter (IC(50)=8 nM) was used to develop a model for the distance and orientation of key features necessary for interaction with the norepinephrine transporter (NET).
Subject(s)
Adrenergic Uptake Inhibitors/chemical synthesis , Adrenergic Uptake Inhibitors/pharmacology , Norepinephrine Plasma Membrane Transport Proteins/chemical synthesis , Norepinephrine Plasma Membrane Transport Proteins/pharmacology , Amines/chemistry , Atomoxetine Hydrochloride , Binding Sites , Cell Line , Chemistry, Pharmaceutical/methods , Desipramine/chemistry , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Propylamines/chemistry , Structure-Activity RelationshipABSTRACT
Incorporation of a carboxylic acid into a series of uracil derivatives as hGnRH-R antagonists resulted in a significant reduction of CYP3A4 inhibitory activity. Highly potent hGnRH antagonists with low CYP3A4 inhibitory liability, such as 8a and 8d, were identified. Thus, 8a had a K(i) of 2.2 nM at GnRH-R and an IC(50) of 36 microM at CYP3A4.
Subject(s)
Cytochrome P-450 CYP3A Inhibitors , Gonadotropin-Releasing Hormone/antagonists & inhibitors , Receptors, LHRH/antagonists & inhibitors , Uracil/analogs & derivatives , Uracil/chemical synthesis , Animals , Cytochrome P-450 CYP3A , Haplorhini , Humans , Inhibitory Concentration 50 , Molecular Structure , Rats , Structure-Activity Relationship , Uracil/pharmacokineticsABSTRACT
A series of piperazinephenethylamines were synthesized to study the contribution of a basic amine to binding affinity at the melanocortin-4 receptor. Several potent compounds from this series possessed subnanomolar K(i) values in a competition binding assay.
Subject(s)
Phenethylamines/chemistry , Phenethylamines/pharmacology , Piperazines/chemistry , Piperazines/pharmacology , Receptor, Melanocortin, Type 4/antagonists & inhibitors , Receptor, Melanocortin, Type 4/metabolism , Animals , Benzylamines/metabolism , Inhibitory Concentration 50 , Kinetics , Phenethylamines/metabolism , Piperazines/metabolism , Structure-Activity RelationshipABSTRACT
A series of pyrrolidinones derived from phenylalanines were synthesized as potent antagonists of the human melanocortin-4 receptor. These compounds showed high potencies and selectivities, and several of them had good oral bioavailabilities. In addition, 12e demonstrated in vivo efficacy in a murine cachexia model.
Subject(s)
Cachexia/drug therapy , Pyrrolidinones/chemistry , Pyrrolidinones/pharmacology , Receptor, Melanocortin, Type 4/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Body Composition , Body Weight , Disease Models, Animal , Humans , Male , Mice , Mice, Inbred C57BL , Molecular Structure , Pyrrolidinones/administration & dosage , Pyrrolidinones/therapeutic use , Structure-Activity RelationshipABSTRACT
A series of alpha-benzylpropionylpiperazines were synthesized and tested as antagonists of the melanocortin-4 receptor. In addition to its high potency and selectivity, R-11a had desirable pharmacokinetic properties including high brain penetration in mice.
Subject(s)
Piperazines/chemistry , Piperazines/pharmacology , Receptor, Melanocortin, Type 4/antagonists & inhibitors , Receptor, Melanocortin, Type 4/metabolism , Amides/chemistry , Animals , Humans , Ligands , Mice , Molecular Structure , Piperazine , Piperazines/chemical synthesis , Piperazines/pharmacokinetics , Structure-Activity RelationshipABSTRACT
The design, synthesis, and SAR of a series of retro bis-aminopyrrolidine ureas are described. Compounds from this series exhibited considerable binding affinity (Ki = 1 nM) and functional activity at MCH-R1, acceptable CYP2D6 inhibition, and good rat brain exposure.
Subject(s)
Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Urea/analogs & derivatives , Animals , Inhibitory Concentration 50 , Molecular Structure , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacokinetics , Rats , Receptors, Somatostatin/metabolism , Structure-Activity Relationship , Urea/chemical synthesis , Urea/chemistry , Urea/pharmacokinetics , Urea/pharmacologyABSTRACT
A series of 3-arylpropionylpiperazines were synthesized as antagonists of the melanocortin-4 receptor. Their potency was found to be increased by replacing the alpha-methyl substituent of the initial lead 11 with a larger s-Bu or i-Bu group. Further potency enhancement was observed when a glycine or beta-alanine was incorporated onto the benzylamine. Some compounds demonstrated good potency, moderate selectivity, and oral bioavailability.
Subject(s)
Piperazines/chemistry , Piperazines/pharmacology , Receptor, Melanocortin, Type 4/antagonists & inhibitors , Animals , Benzylamines/chemistry , Humans , Mice , Molecular Structure , Piperazine , Piperazines/chemical synthesis , Piperazines/pharmacokinetics , Receptor, Melanocortin, Type 4/metabolism , Structure-Activity RelationshipABSTRACT
A series of substituted chromones were designed, synthesized, and evaluated for their ability to bind melanin-concentrating hormone receptor 1. Compounds with subnanomolar binding affinity and 66% oral bioavailability in rats were discovered.
Subject(s)
Chemistry, Pharmaceutical/methods , Chromones/chemical synthesis , Melanins/chemistry , Quinolones/chemical synthesis , Receptors, Pituitary Hormone/antagonists & inhibitors , Receptors, Pituitary Hormone/chemistry , Administration, Oral , Animals , Chromones/chemistry , Drug Design , Humans , Microsomes, Liver/metabolism , Models, Chemical , Quinolones/chemistry , Rats , Time FactorsABSTRACT
A series of 2-pyridinylpiperazines derived from beta-Ala-(2,4-Cl)Phe dipeptide was synthesized for the study of their SARs and possible interactions with the MC4 receptor. Compounds such as 11k (Ki=6.5 nM) possessed high potency.
Subject(s)
Piperazines/chemical synthesis , Piperazines/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Receptor, Melanocortin, Type 4/antagonists & inhibitors , Dipeptides/chemistry , Drug Design , Humans , Structure-Activity Relationship , beta-Alanine/chemistryABSTRACT
Synthesis and structure-activity relationship studies of a series of cyclohexylpiperazines bearing an amide side chain as ligands of the MC4 receptor are discussed. Compounds such as 11i from this series are potent agonists (EC(50)=33nM, IA=96%).
Subject(s)
Benzeneacetamides/chemistry , Piperazines/chemistry , Piperazines/pharmacology , Receptor, Melanocortin, Type 4/agonists , Humans , Ligands , Piperazines/chemical synthesis , Structure-Activity RelationshipABSTRACT
Piperazinebenzylamines bearing a small N-(1-methoxy-2-propyl) side chain were found to be potent and selective antagonists of the human melanocortin-4 (MC4) receptor. Compound 7b, having K(i) values of 6.9 and 2800 nM at the human MC4 and MC3 receptors, respectively, has moderate oral bioavailability in mice, which is improved relative to the arylethyl analogues.
Subject(s)
Benzylamines/pharmacology , Receptor, Melanocortin, Type 4/antagonists & inhibitors , Administration, Oral , Animals , Benzylamines/administration & dosage , Benzylamines/chemistry , Benzylamines/pharmacokinetics , Biological Availability , Cell Line , Humans , Mice , Piperazines/chemistryABSTRACT
The melanocortin-4 receptor (MC4R) plays an important role in the regulation of energy homeostasis. Recent studies have shown that blockade of the MC4R reverses tumor-induced weight loss in mice. Herein, we describe the synthesis and identification of potent and selective non-peptide antagonists of the human MC4R from a series of 2-ethoxycarbonylcyclohexyl-piperazines. Compound 12i was found to possess low nanomolar affinity for the MC4R, and exhibit oral bioavailability in rats. More importantly, when administered orally to mice (10 mg/kg), it led to statistically significant increases in food intake over a 24-h period.
Subject(s)
Piperazines/chemical synthesis , Receptor, Melanocortin, Type 4/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Cachexia/drug therapy , Eating/drug effects , Humans , Piperazines/pharmacokinetics , Piperazines/pharmacology , Protein Binding , Rats , Structure-Activity RelationshipABSTRACT
Several efficient synthetic routes for 2-, 4-, and 6-aryl-1,2,4-triazine-3,5-diones were developed. Derivatives were synthesized and studied as gonadotropin-releasing hormone antagonists in an effort to understand structure-activity relationships of the monocyclic compounds.
Subject(s)
Receptors, LHRH/antagonists & inhibitors , Triazines/chemical synthesis , Humans , Ketones/chemical synthesis , Ketones/pharmacology , Protein Binding , Structure-Activity Relationship , Triazines/pharmacologyABSTRACT
A series of cyclohexylpiperazines was synthesized as potent and selective antagonists of the human MC4 receptor. Compound 14t displayed binding affinity (Ki) of 4.2 and 1100 nM at MC4R and MC3R, respectively.
Subject(s)
Amides/chemistry , Piperidines/pharmacology , Receptor, Melanocortin, Type 4/antagonists & inhibitors , Binding, Competitive , Humans , Molecular Conformation , Piperidines/chemical synthesis , Piperidines/chemistry , Receptor, Melanocortin, Type 3/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
Uracil derivatives were designed and synthesized to avoid atropisomers observed in the 6-methyluracils as antagonists of the human GnRH receptor. Optimization at the 1- and 5-positions of the uracil resulted in potent compounds such as 24 (Ki=0.45 nM).
Subject(s)
Receptors, LHRH/antagonists & inhibitors , Uracil/pharmacology , Humans , Isomerism , Molecular Structure , Uracil/chemistry , X-Ray DiffractionABSTRACT
Optimization on a series of piperazinebenzylamines resulted in analogues with low nanomolar binding at the human MC4 receptor but weak affinity (Ki > 500 nM) at the MC3 receptor. Compound 14c was identified to be a potent MC4R antagonist (Ki = 3.2 nM) with a selectivity of 240-fold over MC3R. It proved to be an insurmountable antagonist in a cAMP assay. Compound 14c potently stimulated food intake in satiated mice when given by intracerebroventricular administration.
Subject(s)
Benzylamines/pharmacology , Feeding Behavior/drug effects , Piperazines/pharmacology , Receptor, Melanocortin, Type 4/antagonists & inhibitors , Satiety Response , Animals , Cell Line , Dose-Response Relationship, Drug , Humans , MiceABSTRACT
Treatment of various 2-methyl oxazolines or thiazolines with chlorocarbonyl isocyanate gives the corresponding bicyclic oxazolino- or thiazolino[3,2-c]pyrimidin-5,7-dione derivatives in very good yield. This reaction has been applied to the rapid syntheses of human gonadotropin-releasing hormone (hGnRH) receptor antagonists for SAR study, resulting in 13e with binding affinity in the low nanomolar range (4.5 nM).
Subject(s)
Bridged Bicyclo Compounds , Oxazoles , Pyrimidinones , Receptors, LHRH/antagonists & inhibitors , Thiazoles , Binding, Competitive , Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/pharmacology , Cyclization , Humans , Molecular Structure , Oxazoles/chemical synthesis , Oxazoles/pharmacology , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacology , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacologyABSTRACT
A convenient one-pot synthetic route was developed for the preparation of asymmetric 1,3-dialkyl-1,3,5-triazine-2,4,6-triones from readily available alkyl- or aryl-isocyanates, primary amines and N-chlorocarbonyl isocyanate in excellent yields. Subsequent alkylation with N-protected amino alcohols afforded the desired 1,3,5-triazine-2,4,6-triones in good yields. This methodology was applied to the synthesis of a chemical library acting as antagonists of the hGnRH receptor.