ABSTRACT
Cuneane is a strained hydrocarbon that can be accessed via metal-catalyzed isomerization of cubane. The carbon atoms of cuneane define a polyhedron of the C2v point group with six facesâtwo triangular, two quadrilateral, and two pentagonal. The rigidity, strain, and unique exit vectors of the cuneane skeleton make it a potential scaffold of interest for the synthesis of functional small molecules and materials. However, the limited previous synthetic efforts toward cuneanes have focused on monosubstituted or redundantly substituted systems such as permethylated, perfluorinated, and bis(hydroxymethylated) cuneanes. Such compounds, particularly rotationally symmetric redundantly substituted cuneanes, have limited potential as building blocks for the synthesis of complex molecules. Reliable, predictable, and selective syntheses of polysubstituted cuneanes bearing more complex substitution patterns would facilitate the study of this ring system in myriad applications. Herein, we report the regioselective, AgI-catalyzed isomerization of asymmetrically 1,4-disubstituted cubanes to cuneanes. In-depth DFT calculations provide a charge-controlled regioselectivity model, and direct dynamics simulations indicate that the nonclassical carbocation invoked is short-lived and dynamic effects augment the charge model.
ABSTRACT
A new molecular rearrangement, the aza-Quasi-Favorskii rearrangement, has been developed for the construction of highly substituted aziridines. Electron-deficient O-sulfonyl oximes react readily with α,α-disubstituted acetophenone-derived enolates to furnish highly substituted aziridines via this unprecedented domino process. In-depth computational studies reveal an asynchronous yet concerted nitrenoid-type rearrangement pathway.
Subject(s)
Aziridines , Aziridines/chemistry , Methylmethacrylates , Molecular Structure , StereoisomerismABSTRACT
BMS-823778 (2), a 1,2,4-triazolopyridinyl-methanol derived analog, was identified as a potent and selective inhibitor of human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD-1) enzyme (IC50 = 2.3 nM) with >10,000-fold selectivity over 11ß-HSD-2. Compound 2 exhibits robust acute pharmacodynamic effects in cynomolgus monkeys (ED50 = 0.6 mg/kg) and in diet-induced obese (DIO) mice (ED50 = 34 mg/kg). Compound 2 also showed excellent inhibition in an ex vivo adipose DIO mouse model (ED50 = 5.2 mg/kg). Oral bioavailability ranges from 44% to 100% in preclinical species. Its favorable development properties, pharmacokinetics, high adipose-to-plasma concentration ratio, and preclinical pharmacology profile have prompted the evaluation of 2 for the treatment of type 2 diabetes and metabolic syndrome in phase 2 clinical trials.
ABSTRACT
BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) enzyme (IC50 3.0 nM) with >10000-fold selectivity over human 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2). 6n-2 exhibits a robust acute pharmacodynamic effect in cynomolgus monkeys (ED50 0.12 mg/kg) and in DIO mice. It is orally bioavailable (%F ranges from 20 to 72% in preclinical species) and has a predicted pharmacokinetic profile of a high peak to trough ratio and short half-life in humans. This ADME profile met our selection criteria for once daily administration, targeting robust inhibition of 11ß-HSD1 enzyme for the first 12 h period after dosing followed by an "inhibition holiday" so that the potential for hypothalamic-pituitary-adrenal (HPA) axis activation might be mitigated. 6n-2 was found to be well-tolerated in phase 1 clinical studies and represents a potential new treatment for type 2 diabetes, metabolic syndrome, and other human diseases modulated by glucocorticoid control.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Adamantane/analogs & derivatives , Azetidines/pharmacology , Enzyme Inhibitors/pharmacology , 11-beta-Hydroxysteroid Dehydrogenase Type 1/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Actins/antagonists & inhibitors , Adamantane/administration & dosage , Adamantane/chemistry , Adamantane/pharmacology , Administration, Oral , Animals , Azetidines/administration & dosage , Azetidines/chemistry , Biological Availability , Crystallography, X-Ray , Dogs , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Female , Half-Life , Humans , Hypothalamo-Hypophyseal System/drug effects , Inhibitory Concentration 50 , Macaca fascicularis , Male , Mice, Obese , Rats , Structure-Activity RelationshipABSTRACT
The design, synthesis and structure-activity relationships of a novel series of 3,4-disubstituted pyrrolidine acid analogs as PPAR ligands is outlined. In both the 1,3- and 1,4-oxybenzyl pyrrolidine acid series, the preferred stereochemistry was shown to be the cis-3R,4S isomer, as exemplified by the potent dual PPARα/γ agonists 3k and 4i. The N-4-trifluoromethyl-pyrimidinyl pyrrolidine acid analog 4i was efficacious in lowering fasting glucose and triglyceride levels in diabetic db/db mice.
Subject(s)
Hypoglycemic Agents/chemical synthesis , PPAR alpha/agonists , PPAR gamma/agonists , Pyrrolidines/chemistry , Animals , Blood Glucose/analysis , Diabetes Mellitus, Type 2/drug therapy , Drug Design , Female , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/therapeutic use , Ligands , Mice , Mice, Obese , PPAR alpha/metabolism , PPAR gamma/metabolism , Pyrrolidines/chemical synthesis , Pyrrolidines/therapeutic use , Stereoisomerism , Structure-Activity Relationship , Triglycerides/bloodABSTRACT
Small alkyl groups and spirocyclic-aromatic rings directly attached to the left side and right side of the 1,2,4-triazolopyridines (TZP), respectively, were found to be potent and selective inhibitors of human 11ß-hydroxysteroid dehydrogenase-type 1 (11ß-HSD-1) enzyme. 3-(1-(4-Chlorophenyl)cyclopropyl)-8-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridine (9f) was identified as a potent inhibitor of the 11ß-HSD-1 enzyme with reduced Pregnane-X receptor (PXR) transactivation activity. The binding orientation of this TZP series was revealed by X-ray crystallography structure studies.
ABSTRACT
Optimization of a 5-oxopyrrolopyridine series based upon structure-activity relationships (SARs) developed from our previous efforts on a number of related bicyclic series yielded compound 2s (BMS-767778) with an overall activity, selectivity, efficacy, PK, and developability profile suitable for progression into the clinic. SAR in the series and characterization of 2s are described.
Subject(s)
Acetamides/chemistry , Acetamides/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Drug Design , Pyrroles/chemistry , Pyrroles/pharmacology , Acetamides/chemical synthesis , Animals , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Catalytic Domain , Dipeptidyl Peptidase 4/chemistry , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Glucose Tolerance Test , Humans , Male , Mice , Models, Molecular , Pyrroles/chemical synthesis , Substrate SpecificityABSTRACT
Derived from the HTS hit 1, a series of hydroxyisoquinolines was discovered as potent and selective 11ß-HSD1 inhibitors with good cross species activity. Optimization of substituents at the 1 and 4 positions of the isoquinoline group in addition to the core modifications, with a special focus on enhancing metabolic stability and aqueous solubility, resulted in the identification of several compounds as potent advanced leads.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Isoquinolines/chemistry , Isoquinolines/pharmacology , Animals , Cell Line , Diabetes Mellitus, Type 2/drug therapy , Enzyme Inhibitors/pharmacokinetics , Humans , Isoquinolines/pharmacokinetics , Mice , Mice, Inbred BALB C , Structure-Activity RelationshipABSTRACT
Design, synthesis, and SAR of 7-oxopyrrolopyridine-derived DPP4 inhibitors are described. The preferred stereochemistry of these atropisomeric biaryl analogs has been identified as Sa. Compound (+)-3t, with a K(i) against DPP4, DPP8, and DPP9 of 0.37 nM, 2.2, and 5.7 µM, respectively, showed a significant improvement in insulin response after single doses of 3 and 10 µmol/kg in ob/ob mice.
Subject(s)
Cytochrome P-450 CYP3A/metabolism , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Ether-A-Go-Go Potassium Channels/metabolism , Pyridines/chemistry , Pyridines/pharmacology , Animals , Catalytic Domain , Diabetes Mellitus/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/pharmacokinetics , Humans , Insulin/blood , Insulin/metabolism , Mice , Mice, Inbred C57BL , Models, Molecular , Pyridines/pharmacokinetics , Pyrroles/chemistry , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , Rats , StereoisomerismABSTRACT
The design, synthesis and structure-activity relationships of a novel series of N-phenyl-substituted pyrrole, 1,2-pyrazole and 1,2,3-triazole acid analogs as PPAR ligands are outlined. The triazole acid analogs 3f and 4f were identified as potent dual PPARalpha/gamma agonists both in binding and functional assays in vitro. The 3-oxybenzyl triazole acetic acid analog 3f showed excellent glucose and triglyceride lowering in diabetic db/db mice.
Subject(s)
Azoles/chemical synthesis , Drug Design , PPAR alpha/agonists , PPAR gamma/agonists , Animals , Azoles/pharmacology , Cell Line/enzymology , Crystallography, X-Ray , Female , Humans , Hydrogen-Ion Concentration , Mice , Mice, Transgenic , PPAR alpha/metabolism , PPAR gamma/metabolism , Structure-Activity RelationshipABSTRACT
Inhibition of sodium-dependent glucose transporter 2 (SGLT2), the transporter that is responsible for renal re-uptake of glucose, leads to glucosuria in animals. SGLT-mediated glucosuria provides a mechanism to shed excess plasma glucose to ameliorate diabetes-related hyperglycemia and associated complications. The current study demonstrates that the proper relationship of a 4'-substituted benzyl group to a beta-1C-phenylglucoside is important for potent and selective SGLT2 inhibition. The lead C-arylglucoside (7a) demonstrates superior metabolic stability to its O-arylglucoside counterpart (4) and it promotes glucosuria when administered in vivo.
Subject(s)
Glucosides/chemistry , Glucosides/pharmacology , Sodium-Glucose Transporter 2 Inhibitors , Animals , Glucose/chemistry , Glycosuria, Renal/drug therapy , Humans , Kidney/drug effects , Rats , Sodium-Glucose Transporter 1/antagonists & inhibitors , Sodium-Glucose Transporter 2ABSTRACT
The C-aryl glucoside 6 (dapagliflozin) was identified as a potent and selective hSGLT2 inhibitor which reduced blood glucose levels in a dose-dependent manner by as much as 55% in hyperglycemic streptozotocin (STZ) rats. These findings, combined with a favorable ADME profile, have prompted clinical evaluation of dapagliflozin for the treatment of type 2 diabetes.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Glucosides/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Kidney/metabolism , Sodium-Glucose Transporter 2 Inhibitors , Administration, Oral , Animals , Benzhydryl Compounds , Blood Glucose/metabolism , Diabetes Mellitus, Experimental/drug therapy , Glucosides/chemistry , Glucosides/pharmacology , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Rats , Sodium-Glucose Transporter 2 , StereoisomerismABSTRACT
A novel class of azetidinone acid-derived dual PPARalpha/gamma agonists has been synthesized for the treatment of diabetes and dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARalpha and PPARgamma receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of compounds in this series are described. A high-yielding method for N-arylation of azetidinone esters is also described.