ABSTRACT
Evolution of a convergent synthetic strategy to access (+)-spongistatin 2 (2), a potent cytotoxic marine macrolide, is described. Highlights of the synthesis include: development of a multicomponent dithiane-mediated linchpin union tactic, devised and implemented specifically for construction of the spongistatin AB and CD spiro ring systems; application of a Ca(II) ion controlled acid promoted equilibration to set the thermodynamically less stable axial-equitorial stereogenicity in the CD spiroketal; use of sulfone addition/Julia methylenation sequences to unite the AB and CD fragments and introduce the C(44)-C(51) side chain; and fragment union and final elaboration to (+)-spongistatin 2 (2) exploiting Wittig olefination to unite the advanced ABCD and EF fragments, followed by regioselective Yamaguchi macrolactonization and global deprotection. Correction of the CD spiro ring stereogenicity was subsequently achieved via acid equilibration in the presence of Ca(II) ion to furnish (+)-spongistatin 2 (2). The synthesis proceeded with a longest linear sequence of 41 steps.
ABSTRACT
The design of amide and heteroaryl amide isosteres as replacements for the carbamate substructure in previously disclosed 2,6-disubstituted piperidine N-arylsulfonamides is described. In several cases, amides lessened CYP liabilities in this class of gamma-secretase inhibitors. Selected compounds showed significant reduction of Abeta levels upon oral dosing in a transgenic murine model of Alzheimer's disease.
Subject(s)
Amides/chemistry , Amides/pharmacology , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Amides/pharmacokinetics , Amyloid beta-Peptides/metabolism , Animals , Carbamates/chemistry , Carbamates/pharmacokinetics , Carbamates/pharmacology , Cytochrome P-450 Enzyme Inhibitors , Heterocyclic Compounds/pharmacokinetics , Mice , Oxadiazoles/chemistry , Oxadiazoles/pharmacokinetics , Oxadiazoles/pharmacology , Piperidines/chemistry , Piperidines/pharmacokinetics , Piperidines/pharmacology , Protease Inhibitors/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
In recent years, obesity therapy has become a major focus of pharmaceutical research. The worldwide market for obesity therapeutics has increased dramatically over tile past decade, and obesity has been linked with numerous co-morbidities. Tile discovery of the role of melanin-concentrating hormone (MCH) in the regulation of energy homeostasis has attracted tile interest of several research groups worldwide. In conjunction with energy balance, a growing body of evidence suggests that MCH is also involved in the regulation of certain types of behavior, including anxiety and depression. Major developments in tile discovery of MCH receptor antagonists over tile past year, including the demonstration of oral efficacy in several rodent models for the treatment of obesity, as well as depression and anxiety, will be highlighted in this review.
Subject(s)
Receptors, Pituitary Hormone/antagonists & inhibitors , Technology, Pharmaceutical/trends , Animals , Humans , Obesity/drug therapy , Obesity/metabolism , Receptors, Pituitary Hormone/metabolism , Technology, Pharmaceutical/methodsABSTRACT
Melanin-concentrating hormone (MCH) is a cyclic, nonadecapeptide expressed in the CNS of all vertebrates that regulates feeding behavior and energy homeostasis via interaction with the central melanocortin system. Regulation of this interaction results in modulation of food intake and body weight gain, demonstrating significant therapeutic potential for the treatment of obesity. The MCH-1 receptor (MCH-R1) has been identified as a key target in MCH regulation, as small molecule antagonists of MCH-R1 have demonstrated activity in vivo. Herein, we document our research in a bicyclo[3.1.0]hexyl urea series with particular emphasis on structure-activity relationships and optimization of receptor occupancy, measured both in vitro and via an ex vivo binding assay following an oral dosing regimen. Several compounds have been tested in vivo and exhibit oral efficacy in relevant acute rodent feeding models. In particular, 24u has proven efficacious in chronic rodent models of obesity, showing a statistically significant reduction in food intake and body weight over a 28 day study.
Subject(s)
Anti-Obesity Agents/chemical synthesis , Phenylurea Compounds/chemical synthesis , Piperazines/chemical synthesis , Receptors, Somatostatin/antagonists & inhibitors , Urea/analogs & derivatives , Urea/chemical synthesis , Administration, Oral , Animals , Anti-Obesity Agents/pharmacology , Biological Availability , Body Weight/drug effects , Brain/metabolism , CHO Cells , Cricetinae , Cricetulus , Eating/drug effects , Half-Life , Male , Obesity/drug therapy , Phenylurea Compounds/pharmacology , Piperazines/pharmacology , Radioligand Assay , Rats , Receptors, Somatostatin/metabolism , Structure-Activity Relationship , Tissue Distribution , Urea/pharmacologyABSTRACT
The design, synthesis, SAR, and biological profile of a substituted 4-morpholine sulfonamide series of γ-secretase inhibitors (GSIs) were described. In several cases, the resulting series of GSIs reduced CYP liabilities and improved γ-secretase inhibition activity compared to our previous research series. Selected compounds demonstrated significant reduction of amyloid-ß (Aß) after acute oral dosing in a transgenic animal model of Alzheimer's disease (AD).
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Morpholines/chemistry , Morpholines/pharmacology , Sulfonamides/chemistry , Alzheimer Disease/drug therapy , Animals , Enzyme Inhibitors/therapeutic use , Female , Male , Mice , Morpholines/therapeutic use , Structure-Activity RelationshipABSTRACT
Melanin concentrating hormone (MCH) is involved in regulation of food intake and energy homeostasis. Antagonists of the MCH receptor are expected to affect food intake and weight gain, making MCH-R1 an attractive target for obesity treatment. Herein, we report the discovery of a novel, orally active series of MCH-R1 antagonists that exhibit in vivo efficacy in rodent obesity models.
Subject(s)
Anti-Obesity Agents/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Receptors, Pituitary Hormone/antagonists & inhibitors , Receptors, Somatostatin/antagonists & inhibitors , Urea/analogs & derivatives , Urea/chemical synthesis , Administration, Oral , Animals , Anti-Obesity Agents/chemistry , Anti-Obesity Agents/pharmacology , Biological Availability , Brain/metabolism , Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/pharmacology , Cycloheptanes/chemical synthesis , Cycloheptanes/chemistry , Cycloheptanes/pharmacology , Cyclohexanes/chemical synthesis , Cyclohexanes/chemistry , Cyclohexanes/pharmacology , Eating/drug effects , Mice , Obesity/drug therapy , Rats , Urea/chemistry , Urea/pharmacologyABSTRACT
Herein, we report a small molecule MCH-R1 antagonist which demonstrates oral efficacy in chronic rodent models. Substituted phenyl biaryl urea derivatives were synthesized and evaluated as MCH-R1 antagonists for the treatment of obesity. The structure-activity relationship studies in this series resulted in identification of urea 1 as a potent and selective MCH-R1 antagonist. Compound 1 exhibited oral efficacy in chronic (28 d) rodent models at 3-30 mpk showing significant reduction in food intake and weight gain relative to controls.
Subject(s)
Obesity/drug therapy , Receptors, Somatostatin/antagonists & inhibitors , Urea/analogs & derivatives , Urea/chemical synthesis , Administration, Oral , Animals , Body Weight/drug effects , Calcium/metabolism , Cells, Cultured , Chronic Disease , Humans , Obesity/metabolism , Rats , Receptors, Somatostatin/genetics , Structure-Activity Relationship , Urea/pharmacologyABSTRACT
Melanin concentrating hormone (MCH) is a cyclic, nonadecapeptide expressed in the CNS of all vertebrates that regulates feeding behavior and energy homeostasis. The MCH-1 receptor (MCH-R1) has been identified as a key target in MCH regulation, as small molecule antagonists of MCH-R1 have demonstrated activity in vivo. Herein, we chronicle our efforts to optimize a hit identified via high throughput screening of our proprietary compound library. Several challenges such as selectivity over other receptors, toxicity of a potential metabolite and determining receptor occupancy via a medium throughput assay will be reviewed.
Subject(s)
Obesity/drug therapy , Obesity/metabolism , Receptors, Pituitary Hormone/antagonists & inhibitors , Receptors, Pituitary Hormone/metabolism , Animals , Drug Evaluation, Preclinical , Humans , Obesity/pathology , Receptors, Pituitary Hormone/classification , Structure-Activity Relationship , Time FactorsABSTRACT
Development of cis-2,4,6-trisubstituted piperidine N-arylsulfonamides as gamma-secretase inhibitors for the potential treatment of Alzheimer's disease (AD) is reported.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Cytochrome P-450 CYP3A/drug effects , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Molecular Structure , Piperidines/chemistry , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
Melanin concentrating hormone (MCH) receptor antagonists have been proposed as potential treatments of obesity. MCH receptor antagonists with a biphenylamine subunit have been reported previously at Schering-Plough. Herein, we report the discovery of bicyclo[4.1.0]heptanes as replacements for the middle phenyl ring of the biphenylamine moiety in order to eliminate its potential mutagenic liability. Structure-activity relationships in this series were found to be very similar to those of the original biphenylamine series, suggesting that the two series have similar binding modes.
Subject(s)
Aminobiphenyl Compounds/chemistry , Bridged Bicyclo Compounds/chemistry , Heptanes/chemistry , Receptors, Pituitary Hormone/antagonists & inhibitors , Animals , Cell Line , Cricetinae , Drug Evaluation, Preclinical , Heptanes/pharmacology , Mice , Molecular Structure , Mutagens/chemistry , Rats , Structure-Activity RelationshipABSTRACT
Herein, we report the discovery of an effective strategy to modulate liabilities related to affinity of previously disclosed bicyclohexane MCHR-1 antagonists for the hERG channel. This paper describes one of several strategies incorporated to limit hERG binding via modifications of a terminal aryl group in an otherwise promising bicyclohexyl urea series.
Subject(s)
Ether-A-Go-Go Potassium Channels/metabolism , Melanins/chemistry , Receptors, Somatostatin/antagonists & inhibitors , Urea/pharmacology , Chemistry, Pharmaceutical , Drug Design , Humans , Inhibitory Concentration 50 , Kinetics , Models, Chemical , Protein Binding , Urea/chemistryABSTRACT
Herein, we report the discovery of the potent and selective biaryl diamide derived MCH-R1 receptor antagonist 1, which was identified upon modification of a previously disclosed biaryl urea series. This paper describes one of the strategies incorporated to remove the highly mutagenic biarylaniline present in an otherwise promising biaryl urea series.
Subject(s)
Amides/chemistry , Amides/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Amides/chemical synthesis , Humans , Structure-Activity Relationship , Urea/chemistryABSTRACT
The compelling genetic and pharmacological evidence implicating melanin-concentrating hormone-1 receptor (MCH-1R) signalling in the regulation of food intake and energy expenditure has generated a great deal of interest by pharmaceutical companies for the discovery of MCH-1R antagonists, evidenced by the increased number of patents describing MCH-1R antagonists for the treatment of obesity and metabolic syndrome. The structural diversity of small molecular weight drug-like MCH-1R antagonists produced and preclinical studies showing hypophagia and weight loss with small molecular weight and peptidal antagonists in rodents is encouraging and suggests that the identification of clinical candidates will be forthcoming.