ABSTRACT
Activin receptor-like kinase 2 (ALK2) is a transmembrane kinase receptor that mediates the signaling of the members of the TGF-ß superfamily. The aberrant activation of ALK2 has been linked to the rare genetic disorder fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) that are associated with severely reduced life expectancy in pediatric patients. ALK2 has also been shown to play an essential role in iron metabolism by regulating hepcidin levels and affecting anemia of chronic disease. Thus, selective inhibition of ALK2 has emerged as a promising strategy for the treatment of multiple disorders. Herein, we report the discovery of a novel pyrazolopyrimidines series as highly potent, selective, and orally bioavailable inhibitors of ALK2. Structure-based drug design and systematic structure-activity relationship studies were employed to identify potent inhibitors displaying high selectivity against other ALK subtypes with good pharmacokinetic profiles.
ABSTRACT
A group of small molecule thienopyrimidine inhibitors of Notum Pectinacetylesterase are described. We explored both 2-((5,6-thieno[2,3-d]pyrimidin-4-yl)thio)acetic acids and 2-((6,7-thieno[3,2-d]pyrimidin-4-yl)thio)acetic acids. In both series, highly potent, orally active Notum Pectinacetylesterase inhibitors were identified.
Subject(s)
Enzyme Inhibitors/pharmacology , Esterases/antagonists & inhibitors , Femur/drug effects , Osteogenesis/drug effects , Pyrimidines/pharmacology , Animals , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Esterases/metabolism , Femur/anatomy & histology , Femur/growth & development , Humans , Mice , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity RelationshipABSTRACT
A group of small molecule thienochromenes inhibitors of Notum Pectinacetylesterase are described. We developed SAR on three series based on carbon, oxygen and sulfur replacement of the 5-position. In each series, highly potent Notum Pectinacetylesterase inhibitors were identified.
Subject(s)
Benzopyrans/chemistry , Enzyme Inhibitors/chemistry , Esterases/antagonists & inhibitors , Animals , Benzopyrans/pharmacokinetics , Benzopyrans/therapeutic use , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , Esterases/metabolism , Femur/physiology , Half-Life , Humans , Inhibitory Concentration 50 , Male , Mice , Osteoporosis/drug therapy , Osteoporosis/physiopathology , Protein Binding , Structure-Activity RelationshipABSTRACT
The synthesis, SAR, and in vivo activity of inhibitors of delta-5 desaturase are described. Ring-constraint of the initial series provided access to a variety of in vitro active chemotypes, from which the indazole was selected. Examples from the indazole series displayed in vivo activity in reducing the enzymatic activity of liver delta-5 desaturase.
Subject(s)
Amides/pharmacology , Drug Design , Enzyme Inhibitors/pharmacology , Fatty Acid Desaturases/antagonists & inhibitors , Metabolic Syndrome/drug therapy , Amides/chemical synthesis , Amides/chemistry , Animals , Delta-5 Fatty Acid Desaturase , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Fatty Acid Desaturases/metabolism , Humans , Liver/enzymology , Metabolic Syndrome/enzymology , Metabolic Syndrome/metabolism , Mice , Molecular Structure , Structure-Activity RelationshipABSTRACT
The incidence of cognitive disorders such as Alzheimer's disease continues to increase unabated. While cures for such diseases have eluded investigators, progress is being made on alleviating certain symptoms of these diseases. Mouse knockouts of the proline transporter (PROT), a high affinity Na(+)/Cl(-)-dependent transporter, indicated its potential as a novel therapeutic target for cognition improvement. Herein we report our investigation into a novel class of PROT inhibitors.
Subject(s)
Amino Acid Transport Systems, Neutral/antagonists & inhibitors , Cognition Disorders/drug therapy , Small Molecule Libraries/pharmacology , Amino Acid Transport Systems, Neutral/deficiency , Amino Acid Transport Systems, Neutral/metabolism , Animals , Biological Transport/drug effects , Dose-Response Relationship, Drug , High-Throughput Screening Assays , Humans , Mice , Mice, Knockout , Molecular Structure , Small Molecule Libraries/chemistry , Structure-Activity RelationshipABSTRACT
During nearly a decade of research dedicated to the study of sphingosine signaling pathways, we identified sphingosine-1-phosphate lyase (S1PL) as a drug target for the treatment of autoimmune disorders. S1PL catalyzes the irreversible decomposition of sphingosine-1-phosphate (S1P) by a retro-aldol fragmentation that yields hexadecanaldehyde and phosphoethanolamine. Genetic models demonstrated that mice expressing reduced S1PL activity had decreased numbers of circulating lymphocytes due to altered lymphocyte trafficking, which prevented disease development in multiple models of autoimmune disease. Mechanistic studies of lymphoid tissue following oral administration of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI) 3 showed a clear relationship between reduced lyase activity, elevated S1P levels, and lower levels of circulating lymphocytes. Our internal medicinal chemistry efforts discovered potent analogues of 3 bearing heterocycles as chemical equivalents of the pendant carbonyl present in the parent structure. Reduction of S1PL activity by oral administration of these analogues recapitulated the phenotype of mice with genetically reduced S1PL expression.
Subject(s)
Aldehyde-Lyases/antagonists & inhibitors , Autoimmune Diseases/drug therapy , Imidazoles/pharmacology , Administration, Oral , Animals , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Imidazoles/administration & dosage , Imidazoles/therapeutic use , Lymphocyte Count , Mice , Structure-Activity RelationshipABSTRACT
GPR139 is an orphan G-protein-coupled receptor (GPCR) that is expressed nearly exclusively in the central nervous system and may play a role in the control of locomotor activity. The signal transduction pathway and pharmacological function of GPR139, however, are still controversial due to the lack of natural or synthetic ligands. The authors report the characterization of human GPR139 signaling pathway and identification of surrogate agonists and antagonists. In both transient and stable transfections of HEK293F cells, overexpression of GPR139 increased basal intracellular cAMP concentrations compared to control cells. Furthermore, forskolin and isoproterenol-stimulated cAMP responses were enhanced in GPR139-expressing cells, suggesting that GPR139 is predominantly coupled to Galpha(s). The authors screened a large library of small molecules for compounds that increase cAMP levels in GPR139-expressing cells and identified a compound with GPR139 agonist activity. This compound increased cAMP production specifically in cells expressing GPR139 but not in cells expressing its highly homologous receptor GPR142. Furthermore, this compound did not induce calcium mobilization in GPR139 cells, indicating no Galpha(q)-mediated response. In addition, antagonist screening with the identified agonist yielded 2 classes of compounds as antagonists. The identification of surrogate agonists and antagonists of human GPR139 provides important tools for further study of this orphan GPCR.
Subject(s)
Drug Evaluation, Preclinical/methods , Nerve Tissue Proteins/agonists , Nerve Tissue Proteins/antagonists & inhibitors , Receptors, G-Protein-Coupled/agonists , Receptors, G-Protein-Coupled/antagonists & inhibitors , Cell Line , Clone Cells , Humans , TransfectionABSTRACT
A series of pyrimidine based inhibitors of PDE7 are discussed. The synthesis, structure-activity relationships (SAR) and selectivity against several other PDE family members as well as activity in T cells are presented. These compounds were found to have effects on T cell proliferation, however it is not clear whether the mechanism is related to PDE7 inhibition.
Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 7/antagonists & inhibitors , Phosphodiesterase Inhibitors/chemistry , Pyrimidines/chemistry , T-Lymphocytes/drug effects , Animals , Cell Proliferation/drug effects , Cyclic Nucleotide Phosphodiesterases, Type 7/genetics , Cyclic Nucleotide Phosphodiesterases, Type 7/metabolism , Gene Knockout Techniques , Mice , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Structure-Activity Relationship , T-Lymphocytes/immunologyABSTRACT
A series of fused pyrimidine based inhibitors of PDE7 have been derived from an earlier screening lead 1. The synthesis, structure-activity relationships (SAR) and selectivity against several other PDE family members are described.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Isoenzymes/metabolism , Phosphodiesterase Inhibitors/chemical synthesis , Pyrimidines/chemistry , 3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Cell Line , Cyclic Nucleotide Phosphodiesterases, Type 7 , Humans , Inhibitory Concentration 50 , Isoenzymes/antagonists & inhibitors , Phosphodiesterase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
Computer aided drug design led to a new class of spiro-barbiturates (e.g., 4a, MMP-13 K(i)=4.7 nM) that are potent inhibitors of MMP-13.
Subject(s)
Barbiturates/chemical synthesis , Enzyme Inhibitors/chemistry , Matrix Metalloproteinase Inhibitors , Barbiturates/pharmacology , Computer Simulation , Computer-Aided Design , Drug Design , Enzyme Inhibitors/pharmacology , Humans , Kinetics , Matrix Metalloproteinase 13 , Models, Molecular , Osteoarthritis/drug therapy , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
A series of purine based inhibitors of PDE7 has been derived from screening lead 1a. The synthesis, structure-activity relationships (SAR), and selectivity against several other PDE family members are described.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Purines/chemical synthesis , Purines/pharmacology , Binding Sites , Cell Line , Cyclic Nucleotide Phosphodiesterases, Type 7 , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Ligands , Structure-Activity Relationship , T-Lymphocytes/enzymologyABSTRACT
The synthesis and structural analysis, involving X-ray crystallographic, nuclear magnetic resonance, and computational studies of four diastereomers of the common western BCD diarylether macrocycle of the complestatins, a family of HIV entry inhibitors, has been achieved exploiting a ruthenium-promoted intramolecular S(N)Ar reaction. The stereogenicity of the individual phenylglycines (residues C and D) results in remarkable effects on the backbone conformation.
Subject(s)
Amino Acids/chemistry , Chlorophenols/chemistry , Models, Molecular , Peptides, Cyclic/chemistry , Heterocyclic Compounds/chemistry , Peptides/chemistry , Protein ConformationABSTRACT
The design, synthesis, and biological evaluation of a series of HIV-1 protease inhibitors [(-)-6, (-)-7, (-)-23, (+)-24] based upon the 3,5,5-trisubstituted pyrrolin-4-one scaffold is described. Use of a monopyrrolinone scaffold leads to inhibitors with improved cellular transport properties relative to the earlier inhibitors based on bispyrrolinones and their peptide counterparts. The most potent inhibitor (-)-7 displayed 13% oral bioavailability in dogs. X-ray structure analysis of the monopyrrolinone compounds cocrystallized with the wild-type HIV-1 protease provided valuable information on the interactions between the inhibitors and the HIV-1 enzyme. In each case, the inhibitors assumed similar orientations for the P2'-P1 substituents, along with an unexpected hydrogen bond of the pyrrolinone NH with Asp225. Interactions with the S2 pocket, however, were not optimal, as illustrated by the inclusion of a water molecule in two of the three inhibitor-enzyme complexes. Efforts to increase affinity by displacing the water molecule with second and third generation inhibitors did not prove successful. Lack of success with this venture is a testament to the difficulty of accurately predicting the many variables that influence and build binding affinity. Comparison of the inhibitor positions in three complexes with that of Indinavir revealed displacements of the protease backbones in the enzyme flap region, accompanied by variations in hydrogen bonding to accommodate the monopyrrolinone ring. The binding orientation of the pyrrolinone-based inhibitors may explain their sustained efficacy against mutant strains of the HIV-1 protease enzyme as compared to Indinavir.