ABSTRACT
A novel sulfonylureido pyridine series exemplified by compound 19 yielded potent inhibitors of FBPase showing significant glucose reduction and modest glycogen lowering in the acute db/db mouse model for Type-2 diabetes. Our inhibitors occupy the allosteric binding site and also extend into the dyad interface region of tetrameric FBPase.
Subject(s)
Aminopyridines/pharmacology , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Fructose-Bisphosphatase/antagonists & inhibitors , Administration, Oral , Allosteric Site , Aminopyridines/chemistry , Animals , Crystallography, X-Ray , Diabetes Mellitus, Type 2 , Disease Models, Animal , Enzyme Inhibitors/chemistry , Fructose-Bisphosphatase/chemistry , Fructose-Bisphosphatase/metabolism , Humans , Inhibitory Concentration 50 , Liver/enzymology , Mice , Molecular StructureABSTRACT
Synthesis and SAR are described for a structurally distinct class of DPP-IV inhibitors based on aminobenzo[a]quinolizines bearing (hetero-)aromatic substituents in the S1 specificity pocket. The m-(fluoromethyl)-phenyl derivative (S,S,S)-2g possesses the best fit in the S1 pocket. However, (S,S,S)-2i, bearing a more hydrophilic 5-methyl-pyridin-2-yl residue as substituent for the S1 pocket, displays excellent in vivo activity and superior drug-like properties.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Quinolizines/chemistry , Animals , Crystallography, X-Ray , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/metabolism , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Humans , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacology , Quinolizines/metabolism , Quinolizines/pharmacology , Rats , Rats, ZuckerABSTRACT
Sulfonylureido thiazoles were identified from a HTS campaign and optimized through a combination of structure-activity studies, X-ray crystallography and molecular modeling to yield potent inhibitors of fructose-1,6-bisphosphatase. Compound 12 showed favorable ADME properties, for example, F=70%, and a robust 32% glucose reduction in the acute db/db mouse model for Type-2 diabetes.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Fructose-Bisphosphatase/antagonists & inhibitors , Hypoglycemic Agents/chemistry , Sulfonylurea Compounds/chemistry , Thiazoles/chemistry , Animals , Binding Sites , Crystallography, X-Ray , Disease Models, Animal , Fructose-Bisphosphatase/metabolism , High-Throughput Screening Assays , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacokinetics , Mice , Structure-Activity Relationship , Sulfonylurea Compounds/chemical synthesis , Sulfonylurea Compounds/pharmacokinetics , Thiazoles/chemical synthesis , Thiazoles/pharmacokinetics , Thiazoles/pharmacologyABSTRACT
Tetrakis(dimethylamino)ethylene (TDAE 1), has been exploited for the first time as a mild reagent for the reduction of arenediazonium salts to aryl radical intermediates through a single electron transfer (SET) pathway. Cyclization of the aryl radicals produced in this way led, in appropriate substrates, to syntheses of indolines and indoles. Cascade radical cyclizations of aryl radicals derived from arenediazonium salts are also reported. The relative ease of removal of the oxidized by-products of TDAE from the reaction mixture makes the methodology synthetically attractive.
ABSTRACT
In a search for novel DPP-IV inhibitors, 2-aminobenzo[a]quinolizines were identified as submicromolar HTS hits. Due to the difficult synthetic access to this compound class, 1,3-disubstituted 4-aminopiperidines were used as model compounds for optimization. The developed synthetic methodology and the SAR could be transferred to the 2-aminobenzo[a]quinolizine series, leading to highly active DPP-IV inhibitors.
Subject(s)
Adenosine Deaminase Inhibitors , Dipeptidyl-Peptidase IV Inhibitors , Glycoproteins/antagonists & inhibitors , Piperidines/chemistry , Protease Inhibitors/chemistry , Adenosine Deaminase/chemistry , Dipeptidyl Peptidase 4/chemistry , Glycoproteins/chemistry , Humans , Piperidines/chemical synthesis , Piperidines/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Protein Conformation , Structure-Activity RelationshipABSTRACT
We describe the structure-based design and synthesis of highly potent, orally bioavailable tissue factor/factor VIIa inhibitors which interfere with the coagulation cascade by selective inhibition of the extrinsic pathway.
Subject(s)
Anticoagulants/chemistry , Anticoagulants/pharmacology , Factor VIIa/antagonists & inhibitors , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Thromboplastin/antagonists & inhibitors , Administration, Oral , Animals , Anticoagulants/chemical synthesis , Biological Availability , Crystallography, X-Ray , Drug Design , Glycine/analogs & derivatives , Glycine/chemistry , Humans , Molecular Structure , Rats , Serine Proteinase Inhibitors/chemical synthesisABSTRACT
[reaction: see text] A novel, mild, ecofriendly protocol for the deoxygenation of epoxides to alkenes using indium metal and indium(I) chloride or ammonium chloride in alcohol has been developed. It was necessary for the presence of good radical-stabilizing groups adjacent to the oxirane ring for the deoxygenation reaction to occur. It is proposed that this reaction occurs through an SET process with indium as an electron donor.
ABSTRACT
The first examples of highly enantioselective [2,3]-sigmatropic rearrangements of acyclic allylic ammonium ylids are reported. Thus, a range of N-{2'-[(N'-allyl-N',N'-dialkyl)ammonium]}acetyl camphor sultams undergo rearrangement at 0 degrees C in DME solution with high diastereofacial control (up to 99:1 dr) to give allylglycines in generally high yield. The power of the method has been demonstrated in a rapid and efficient synthesis of (R)-allyl glycine.
Subject(s)
Allyl Compounds/chemistry , Glycine/analogs & derivatives , Quaternary Ammonium Compounds/chemistry , Allyl Compounds/chemical synthesis , Allylglycine/chemical synthesis , Allylglycine/chemistry , Glycine/chemical synthesis , Glycine/chemistryABSTRACT
A ring-contractive and highly diastereoselective [2,3]-sigmatropic rearrangement occurs when N-methyl-1,2,3,6-tetrahydropyridine is treated with sub-stoichiometric amounts of copper or rhodium salts, in the presence of ethyl diazoacetate, giving ethyl cis-N-methyl-3-ethenyl proline (4).
