ABSTRACT
Mutant huntingtin (mHTT) protein carrying the elongated N-terminal polyglutamine (polyQ) tract misfolds and forms protein aggregates characteristic of Huntington's disease (HD) pathology. A high-affinity ligand specific for mHTT aggregates could serve as a positron emission tomography (PET) imaging biomarker for HD therapeutic development and disease progression. To identify such compounds with binding affinity for polyQ aggregates, we embarked on systematic structural activity studies; lead optimization of aggregate-binding affinity, unbound fractions in brain, permeability, and low efflux culminated in the discovery of compound 1, which exhibited target engagement in autoradiography (ARG) studies in brain slices from HD mouse models and postmortem human HD samples. PET imaging studies with 11C-labeled 1 in both HD mice and WT nonhuman primates (NHPs) demonstrated that the right-hand-side labeled ligand [11C]-1R (CHDI-180R) is a suitable PET tracer for imaging of mHTT aggregates. [11C]-1R is now being advanced to human trials as a first-in-class HD PET radiotracer.
Subject(s)
Huntingtin Protein/analysis , Huntington Disease/diagnostic imaging , Positron-Emission Tomography/methods , Protein Aggregation, Pathological/diagnostic imaging , Animals , Disease Models, Animal , Dogs , Female , Humans , Huntingtin Protein/genetics , Huntington Disease/genetics , Ligands , Madin Darby Canine Kidney Cells , Male , Mice , Mice, Inbred C57BL , Mutation , Peptides/genetics , Protein Aggregation, Pathological/genetics , Radiopharmaceuticals/analysis , Rats, Sprague-DawleyABSTRACT
Starting from benzylpyrimidine 2, molecular modeling and X-ray crystallography were used to design highly potent inhibitors of Interleukin-2 inducible T-cell kinase (ITK). Sulfonylpyridine 4i showed sub-nanomolar affinity against ITK, was selective versus Lck and its activity in the Jurkat cell-based assay was greatly improved over 2.
Subject(s)
Drug Design , Protein Kinase Inhibitors/chemical synthesis , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyridines/chemistry , Binding Sites , Crystallography, X-Ray , Kinetics , Molecular Dynamics Simulation , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Protein Structure, Tertiary , Protein-Tyrosine Kinases/metabolism , Pyrazoles/chemistry , Pyridines/chemical synthesis , Pyridines/metabolism , Structure-Activity Relationship , Sulfones/chemistryABSTRACT
Inhibition of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signalling cascade, may represent a novel treatment for allergic asthma. Here we report the structure-based optimization of a series of benzothiazole amides that demonstrate sub-nanomolar inhibitory potency against ITK with good cellular activity and kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of several inhibitor-ITK complexes.
Subject(s)
Benzothiazoles/chemistry , Benzothiazoles/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Benzothiazoles/chemical synthesis , Crystallography, X-Ray , Drug Design , Humans , Mice , Models, Molecular , Protein-Tyrosine Kinases/chemistry , Signal Transduction , Structure-Activity RelationshipABSTRACT
Tissue transglutaminase 2 (TG2) is a multifunctional protein primarily known for its calcium-dependent enzymatic protein cross-linking activity via isopeptide bond formation between glutamine and lysine residues. TG2 overexpression and activity have been found to be associated with Huntington's disease (HD); specifically, TG2 is up-regulated in the brains of HD patients and in animal models of the disease. Interestingly, genetic deletion of TG2 in two different HD mouse models, R6/1 and R6/2, results in improved phenotypes including a reduction in neuronal death and prolonged survival. Starting with phenylacrylamide screening hit 7d, we describe the SAR of this series leading to potent and selective TG2 inhibitors. The suitability of the compounds as in vitro tools to elucidate the biology of TG2 was demonstrated through mode of inhibition studies, characterization of druglike properties, and inhibition profiles in a cell lysate assay.
Subject(s)
Acrylamides/chemical synthesis , GTP-Binding Proteins/antagonists & inhibitors , Huntington Disease/drug therapy , Sulfonamides/chemical synthesis , Transglutaminases/antagonists & inhibitors , Acrylamides/chemistry , Acrylamides/pharmacology , Animals , Caco-2 Cells , Cell Membrane Permeability , HEK293 Cells , Humans , In Vitro Techniques , Male , Mice , Microsomes, Liver/metabolism , Models, Molecular , Piperazines/chemical synthesis , Piperazines/chemistry , Piperazines/pharmacology , Protein Glutamine gamma Glutamyltransferase 2 , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Pyrimidines/pharmacology , Rats , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
We report a series of irreversible transglutaminase 2 inhibitors starting from a known lysine dipeptide bearing an acrylamide warhead. We established new SARs resulting in compounds demonstrating improved potency and better physical and calculated properties. Transglutaminase selectivity profiling and in vitro ADME properties of selected compounds are also reported.
ABSTRACT
A new series of potent TG2 inhibitors are reported that employ a 4-aminopiperidine core bearing an acrylamide warhead. We establish the structure-activity relationship of this new series and report on the transglutaminase selectivity and in vitro ADME properties of selected compounds. We demonstrate that the compounds do not conjugate glutathione in an in vitro setting and have superior plasma stability over our previous series.
ABSTRACT
A series of potent and subtype selective H3 receptor antagonists containing a novel tetrazole core and diamine motif is reported. A one-pot multi-component Ugi reaction was utilised to rapidly develop the structure-activity relationships (SAR) of these compounds. Optimisation for liver microsome stability (t(1/2)>60 min), minimal CYP inhibition (IC(50)>50 microM) and high cell permeability (Caco-2 P(app) >20x10(-6) cm/s) identified several compounds with drug-like properties.
Subject(s)
Histamine H3 Antagonists/pharmacology , Tetrazoles/pharmacology , Caco-2 Cells , Cell Membrane Permeability , Drug Discovery , Half-Life , Histamine H3 Antagonists/chemistry , Histamine H3 Antagonists/pharmacokinetics , Humans , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Structure-Activity Relationship , Tetrazoles/chemistry , Tetrazoles/pharmacokineticsABSTRACT
Prurigo nodularis (PN) is a benign neurodermatitis of unknown etiology characterized by firm, hyperkeratotic pruritic nodules most commonly localized symmetrically on the bilateral extensor lower extremities. PN represents a primary dermatological condition or a dermatological manifestation of repeated traumatic manipulation secondary to chronic pruritus. One must consider underlying causes of pruritus, which may include psychiatric disorders and internal disease. Given its chronicity and relapsing nature, treatment of PN can be challenging. Interruption of the itch-scratch cycle is difficult; long term prognosis remains guarded.
Subject(s)
Prurigo/etiology , Pruritus/complications , Diagnosis, Differential , Humans , Prurigo/diagnosis , Prurigo/pathology , Prurigo/therapyABSTRACT
Nevus spilus (NS), also known as speckled lentiginous nevus (SLN), is a relatively common cutaneous lesion that is characterized by multiple pigmented macules or papules within a pigmented patch. It may be congenital or acquired; however, its etiology remains unknown. NS deserves its own place in the spectrum of classification of important melanocytic nevi; as a lentigo and melanocytic nevus, it has the slight potential to develop into melanoma. Accordingly, we recommend consideration of punch excisions of the speckles alone if excision of the entire NS is declined.
