ABSTRACT
Caspases are a family of cysteine-dependent proteases with important cellular functions in inflammation and apoptosis, while also implicated in human diseases. Classical chemical tools to study caspase functions lack selectivity for specific caspase family members due to highly conserved active sites and catalytic machinery. To overcome this limitation, we targeted a non-catalytic cysteine residue (C264) unique to caspase-6 (C6), an enigmatic and understudied caspase isoform. Starting from disulfide ligands identified in a cysteine trapping screen, we used a structure-informed covalent ligand design to produce potent, irreversible inhibitors (3a) and chemoproteomic probes (13-t) of C6 that exhibit unprecedented selectivity over other caspase family members and high proteome selectivity. This approach and the new tools described will enable rigorous interrogation of the role of caspase-6 in developmental biology and in inflammatory and neurodegenerative diseases.
Subject(s)
Caspases , Cysteine , Humans , Caspase 6 , Apoptosis , Cysteine Proteinase Inhibitors/pharmacologyABSTRACT
The structure activity relationship of the prime region of conformationally restricted hydroxyethylamine (HEA) BACE inhibitors is described. Variation of the P1' region provided selectivity over Cat-D with a series of 2,2-dioxo-isothiochromanes and optimization of the P2' substituent of chromane-HEA(s) with polar substituents provided improvements in the compound's in vitro permeability. Significant potency gains were observed with small aliphatic substituents such as methyl, n-propyl, and cyclopropyl when placed at the C-2 position of the chromane.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Chromans/chemistry , Drug Design , Enzyme Inhibitors/chemical synthesis , Binding Sites , Cells, Cultured , Ethylamines/chemical synthesis , Ethylamines/chemistry , Ethylamines/pharmacology , Inhibitory Concentration 50 , Models, Molecular , Structure-Activity RelationshipABSTRACT
The synthesis and in vivo SAR of 2-(2,2,2)-trifluoroethyl-benzimidazoles are described. Prostate antagonism and/or levator ani agonism can be modulated by varying the substitution at the 2-position of 5,6-dichloro-benzimidazoles. Potent androgen agonists on the muscle were discovered that strongly bind to the androgen receptor (2-17 nM) and show potent in vivo efficacy (0.03-0.11 mg/day). True SARMs showing both prostate antagonism and levator ani agonism were revealed.
Subject(s)
Benzimidazoles/chemical synthesis , Receptors, Androgen/drug effects , Androgen Receptor Antagonists , Androgens , Animals , Benzimidazoles/agonists , Benzimidazoles/antagonists & inhibitors , Dose-Response Relationship, Drug , Indicators and Reagents , Male , Models, Molecular , Muscle, Smooth/drug effects , Muscle, Smooth/metabolism , Organ Size/drug effects , Prostate/drug effects , Prostate/metabolism , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
The synthesis and in vivo SAR of 5,6-dichloro-benzimidazole derivatives as novel selective androgen receptor antagonists are described. During screening of 2-alkyl benzimidazoles, it was found that a trifluoromethyl group greatly enhances antagonist activity in the prostate. Benzimidazole 1 is a potent AR antagonist in the rat prostate (ID50 = 0.15 mg/day).
Subject(s)
Androgen Antagonists/chemical synthesis , Androgen Antagonists/pharmacology , Androgen Receptor Antagonists , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Animals , Indicators and Reagents , Male , Molecular Weight , Orchiectomy , Prostate/drug effects , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfides/chemical synthesis , Sulfones/chemical synthesisABSTRACT
The synthesis and in vivo SAR of N-benzyl, N-aceto, and N-ethylene ether derivatives of 2-(2,2,2-trifluoroethyl)-5,6-dichloro-benzimidazole as novel androgen receptor antagonists are described. SAR studies led to the discovery of 4-bromo-benzyl benzimidazole 17 as a more potent androgen receptor antagonist in the rat prostate (ID(50)=0.13mg/day), compared with bicalutamide (ID(50)=0.23mg/day).
