ABSTRACT
A simple, novel, and efficient route for the synthesis of 5-amino-3-aryl-1-(tert-butyl)-1H-pyrazole-4-carboxamides 1 has been devised. Preparation of pyrazole bromide 3 from potassium tricyanomethanide can be accomplished in only two steps in good yield and features a selective Sandmeyer reaction on the corresponding diaminopyrazole. This allows for a more versatile synthesis of 5-amino-3-aryl-1-(tert-butyl)-1H-pyrazole-4-carboxamides 1 than was previously possible.
Subject(s)
Amides/chemical synthesis , Hydrocarbons, Brominated/chemical synthesis , Pyrazoles/chemical synthesis , Amides/chemistry , Combinatorial Chemistry Techniques , Hydrocarbons, Brominated/chemistry , Molecular Structure , Pyrazoles/chemistry , StereoisomerismABSTRACT
A new class of PDF inhibitor with potent, broad spectrum antibacterial activity is described. Optimization of blood stability and potency provided compounds with improved pharmacokinetics that were suitable for in vivo experiments. Compound 5c, which has robust antibacterial activity, demonstrated efficacy in two respiratory tract infection models.
Subject(s)
Amides/chemical synthesis , Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/chemical synthesis , Bacterial Proteins/antagonists & inhibitors , Proline/analogs & derivatives , Proline/chemical synthesis , Respiratory Tract Infections/drug therapy , Administration, Oral , Amides/pharmacology , Amidohydrolases/metabolism , Animals , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/metabolism , Crystallography, X-Ray , Disease Models, Animal , Haemophilus influenzae/drug effects , Haemophilus influenzae/growth & development , Humans , Injections, Intravenous , Microbial Sensitivity Tests , Models, Molecular , Proline/pharmacology , Rats , Respiratory Tract Infections/microbiology , Streptococcus pneumoniae/drug effects , Streptococcus pneumoniae/growth & development , Structure-Activity RelationshipABSTRACT
Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.
Subject(s)
Antineoplastic Agents/chemical synthesis , Indazoles/chemical synthesis , Morpholines/chemical synthesis , Piperidines/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidines/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Indazoles/chemistry , Indazoles/pharmacology , Mice , Mice, SCID , Models, Molecular , Molecular Structure , Morpholines/chemistry , Morpholines/pharmacology , Neoplasm Transplantation , Phosphorylation , Piperidines/chemistry , Piperidines/pharmacology , Protein Binding , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyruvate Dehydrogenase Acetyl-Transferring Kinase , Stereoisomerism , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
A series of novel potent benzimidazole based inhibitors of interleukin-2 T-cell kinase (Itk) were prepared. In this report, we discuss the structure-activity relationship (SAR), selectivity, and cell-based activity for the series. We also discuss the SAR associated with an X-ray structure of one of the small-molecule inhibitors bound to ITK.
Subject(s)
Amides/chemistry , Benzimidazoles/chemistry , Carboxylic Acids/chemistry , Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/chemical synthesis , Microsomes, Liver/metabolism , Protein-Tyrosine Kinases/chemistry , Animals , Benzimidazoles/chemical synthesis , Carboxylic Acids/chemical synthesis , Crystallography, X-Ray , Drug Design , Enzyme Inhibitors/pharmacology , Inhibitory Concentration 50 , Mice , Models, Chemical , Molecular Conformation , Structure-Activity RelationshipABSTRACT
The discovery of novel 5,7-disubstituted[1,6]naphthyridines as potent inhibitors of Spleen Tyrosine Kinase (SYK) is discussed. The SAR reveals the necessity for a 7-aryl group with preference towards para substitution and that this in combination with 5-aminoalkylamino substituents further improved the potency of the compounds. The initial SAR as well as a survey of the other positions is discussed in detail.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Enzyme Precursors/antagonists & inhibitors , Naphthyridines/chemistry , Naphthyridines/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Spleen/enzymology , Animals , Humans , Inhibitory Concentration 50 , Intracellular Signaling Peptides and Proteins , Structure-Activity Relationship , Syk KinaseABSTRACT
A narrow structure-activity relationship was established for the 4-aryl group in 4-aryl-pyridine glucagon antagonists, with only small substituents being well-tolerated, and only at the 3'- and 4'-positions. However, substitution with a 2'-hydroxy group gave a ca. 3-fold increase in activity (e.g., 4'-fluoro-2'-hydroxy analogue 33, IC50=190 nM). For efficient preparation of 2'-substituted phenylpyridines, a novel synthesis via pyrones and 4-methoxy-pyridines was developed.
Subject(s)
Glucagon/antagonists & inhibitors , Pyridines/chemical synthesis , Pyridines/pharmacology , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
A series of conformationally-restricted analogues of hPTH was prepared, based on the parent peptide agonist, cyclo(Lys(18)-Asp(22))[Ala(1),Nle(8),Lys(18),Asp(22),Leu(27)]hPTH(1-31)NH(2) (2, EC(50)=0.29nM). Truncation of 2 at either the N- or C-termini resulted in peptides with reduced agonist activity as measured by stimulation of adenylate cyclase activity in the rat osteosarcoma cell line (ROS 17/2.8). Alanine- and glycine-scanning at the N-terminus of 2 was consistent with data previously obtained on linear hPTH(1-34). Other locations within the primary sequence of hPTH(1-31)NH(2) were evaluated by the placement of the [i, i+4] lactam constraining element. Ring size and lactam orientations at the 18-22 positions were also examined.
