ABSTRACT
We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb(+)) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y)), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.
Subject(s)
Cyclin-Dependent Kinase 4/antagonists & inhibitors , Heterocyclic Compounds, 3-Ring/chemical synthesis , Naphthyridines/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Animals , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Cytochrome P-450 CYP3A , Cytochrome P-450 CYP3A Inhibitors , Dogs , Drug Discovery , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Macaca fascicularis , Naphthyridines/pharmacology , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Rats , Structure-Activity Relationship , U937 Cells , fms-Like Tyrosine Kinase 3/geneticsABSTRACT
Sphingosine-1-phosphate (S1P) signaling plays a vital role in mitogenesis, cell migration and angiogenesis. Sphingosine kinases (SphKs) catalyze a key step in sphingomyelin metabolism that leads to the production of S1P. There are two isoforms of SphK and observations made with SphK deficient mice show the two isoforms can compensate for each other's loss. Thus, inhibition of both isoforms is likely required to block SphK dependent angiogenesis. A structure based approach was used to design and synthesize a series of SphK inhibitors resulting in the identification of the first potent inhibitors of both isoforms of human SphK. Additionally, to our knowledge, this series of inhibitors contains the only sufficiently potent inhibitors of murine SphK1 with suitable physico-chemical properties to pharmacologically interrogate the role of SphK1 in rodent models and to reproduce the phenotype of SphK1 (-/-) mice.
Subject(s)
Drug Design , Enzyme Inhibitors/chemical synthesis , Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors , Phosphotransferases (Alcohol Group Acceptor)/chemistry , Small Molecule Libraries/chemical synthesis , Animals , Cells, Cultured , Crystallography, X-Ray , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Mice , Molecular Structure , Protein Isoforms/chemistry , Rats , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Structure-Activity RelationshipABSTRACT
A series of benzodiazepine antagonists of the human ghrelin receptor GHSR1a were synthesized and their antagonism and metabolic stability were evaluated. The potency of these analogs was determined using a functional aequorin (Euroscreen) luminescent assay measuring the intracellular Ca(2+) concentration, and their metabolic stability was measured using an in vitro rat and human S9 hepatocyte assay. These efforts led to the discovery of a potent ghrelin antagonist with good rat pharmacokinetic properties.
Subject(s)
Benzodiazepines/chemistry , Benzodiazepines/pharmacology , Receptors, Ghrelin/antagonists & inhibitors , Receptors, Ghrelin/metabolism , Animals , Benzodiazepines/metabolism , Benzodiazepines/pharmacokinetics , Calcium/metabolism , Cell Line , Hepatocytes/metabolism , Humans , Luminescent Measurements , Obesity/drug therapy , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Piperazine-bisamide analogs were discovered as partial agonists of human growth hormone secretagogue receptor (GHSR) in a high throughput screen. The partial agonists were optimized for potency and converted into antagonists through structure-activity relationship (SAR) studies. The efforts also led to the identification of potent antagonist with favorable PK profile suitable as a tool compound for in vivo studies.
Subject(s)
Amides/chemistry , Anti-Obesity Agents/chemistry , Indoles/chemistry , Piperazines/chemistry , Receptors, Ghrelin/antagonists & inhibitors , Amides/chemical synthesis , Amides/therapeutic use , Animals , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/therapeutic use , High-Throughput Screening Assays , Humans , Indoles/chemical synthesis , Indoles/therapeutic use , Obesity/drug therapy , Piperazines/chemical synthesis , Piperazines/therapeutic use , Rats , Receptors, Ghrelin/metabolism , Structure-Activity RelationshipABSTRACT
Free fatty acid receptor 2 (FFA2) is a G-protein coupled receptor for which only short-chain fatty acids (SCFAs) have been reported as endogenous ligands. We describe the discovery and optimization of phenylacetamides as allosteric agonists of FFA2. These novel ligands can suppress adipocyte lipolysis in vitro and reduce plasma FFA levels in vivo, suggesting that these allosteric modulators can serve as pharmacological tools for exploring the potential function of FFA2 in various disease conditions.
Subject(s)
Acetamides/chemical synthesis , Receptors, Cell Surface/agonists , Receptors, G-Protein-Coupled/agonists , Acetamides/chemistry , Acetamides/pharmacokinetics , Allosteric Regulation , Animals , Cyclic AMP/metabolism , Drug Discovery , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Rats , Receptors, Cell Surface/metabolism , Receptors, G-Protein-Coupled/metabolism , Structure-Activity RelationshipABSTRACT
The discovery and optimization of a series of potent PPARdelta full agonists with partial agonistic activity against PPARgamma is described.
Subject(s)
PPAR delta/agonists , PPAR gamma/agonists , Thiazoles/chemistry , Animals , Computer Simulation , Crystallography, X-Ray , PPAR delta/metabolism , PPAR gamma/metabolism , Rats , Rats, Sprague-Dawley , Thiazoles/chemical synthesis , Thiazoles/pharmacologyABSTRACT
This review chronicles original literature dating back to 1992 outlining the applications of parallel synthesis and combinatorial chemistry to the synthesis of compound libraries focused towards specific superfamilies of molecular targets. Target families that have received significant literature coverage include kinases, proteases, nuclear hormone receptors and cell surface receptors, notably GPCRs.
