ABSTRACT
Minor structural modifications-sometimes single atom changes-can have a dramatic impact on the properties of compounds. This is illustrated here on structures related to known mTOR inhibitor Sapanisertib. Subtle changes in the hinge binder lead to strikingly different overall profiles with changes in physical properties, metabolism, and kinase selectivity.
ABSTRACT
A series of squaramide-based hydroxamic acids were designed, synthesized and evaluated against human HDAC enzyme. Squaramides were found to be potent in the Hut78 cell line, but initially suffered from low solubility. Leads with improved solubility and metabolic profiles were shown to be class I, IIB and IV selective.
Subject(s)
Antineoplastic Agents/pharmacology , Histone Deacetylase 1/antagonists & inhibitors , Histone Deacetylase 2/antagonists & inhibitors , Histone Deacetylase Inhibitors/pharmacology , Lymphoma, T-Cell, Cutaneous/drug therapy , Quinine/analogs & derivatives , Skin Neoplasms/drug therapy , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Histone Deacetylase 1/metabolism , Histone Deacetylase 2/metabolism , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Humans , Lymphoma, T-Cell, Cutaneous/metabolism , Lymphoma, T-Cell, Cutaneous/pathology , Models, Molecular , Molecular Structure , Quinine/chemical synthesis , Quinine/chemistry , Quinine/pharmacology , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , Solubility , Structure-Activity RelationshipABSTRACT
Retinoids have a dominant role in topical acne therapy and to date, only RARß and RARγ dual agonists have reached the market. Given the tissue distribution of RAR isoforms, it was hypothesized that developing RARγ -selective agonists could yield a new generation of topical acne treatments that would increase safety margins while maintaining the robust efficacy of previous drugs. Structural knowledge derived from the X-ray structure of known γ-selective CD437, suggested the design of a novel triaryl series of agonists which was optimized and ultimately led to the discovery of Trifarotene/CD5789.
Subject(s)
Acne Vulgaris/drug therapy , Drug Design , Receptors, Retinoic Acid/agonists , Retinoids/pharmacology , Dose-Response Relationship, Drug , Humans , Molecular Docking Simulation , Molecular Structure , Retinoids/chemical synthesis , Retinoids/chemistry , Structure-Activity Relationship , Retinoic Acid Receptor gammaABSTRACT
The use of an interleukin ß antibody is currently being investigated in the clinic for the treatment of acne, a dermatological disorder affecting 650M persons globally. Inhibiting the protease responsible for the cleavage of inactive pro-IL1ß into active IL-1ß, caspase-1, could be an alternative small molecule approach. This report describes the discovery of uracil 20, a potent (38 nM in THP1 cells assay) caspase-1 inhibitor for the topical treatment of inflammatory acne. The uracil series was designed according to a published caspase-1 pharmacophore model involving a reactive warhead in P1 for covalent reversible inhibition and an aryl moiety in P4 for selectivity against the apoptotic caspases. Reversibility was assessed in an enzymatic dilution assay or by using different substrate concentrations. In addition to classical structure-activity-relationship exploration, topical administration challenges such as phototoxicity, organic and aqueous solubility, chemical stability in solution, and skin metabolic stability are discussed and successfully resolved.
Subject(s)
Acne Vulgaris/drug therapy , Caspase 1/metabolism , Caspase Inhibitors/administration & dosage , Caspase Inhibitors/pharmacology , Drug Design , Acne Vulgaris/enzymology , Administration, Topical , Animals , Caspase 1/chemistry , Caspase Inhibitors/pharmacokinetics , Caspase Inhibitors/therapeutic use , Cell Line , Humans , Mice , Models, Molecular , Protein Conformation , Solvents/chemistry , Tissue DistributionABSTRACT
Progress in the identification of suitable RORγ inverse agonists as clinical candidates has been hampered by the high lipophilicity that seems required for high potency on this nuclear receptor. In this context, we decided to focus on the replacement of the hydroxymethyl group found on known modulators to determine if more polarity could be tolerated in this position. SAR of the replacement of this moiety is presented in this article leading to the identification of sulfoximine derivatives as potent modulators with pharmacological activity in the in vivo mouse Imiquimod psoriasis model.
Subject(s)
Imines/pharmacology , Nuclear Receptor Subfamily 1, Group F, Member 3/antagonists & inhibitors , Sulfonamides/pharmacology , Sulfoxides/pharmacology , Animals , Drug Inverse Agonism , Female , Humans , Imines/chemical synthesis , Imines/chemistry , Ligands , Mice, Inbred BALB C , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfoxides/chemical synthesis , Sulfoxides/chemistryABSTRACT
With possible implications in multiple autoimmune diseases, the retinoic acid receptor-related orphan receptor RORγ has become a sought-after target in the pharmaceutical industry. Herein are described the efforts to identify a potent RORγ inverse agonist compatible with topical application for the treatment of skin diseases. These efforts culminated in the discovery of N-(2,4-dimethylphenyl)-N-isobutyl-2-oxo-1-[(tetrahydro-2H-pyran-4-yl)methyl]-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide (CD12681), a potent inverse agonist with inâ vivo activity in an IL-23-induced mouse skin inflammation model.
Subject(s)
Nuclear Receptor Subfamily 1, Group F, Member 3/agonists , Psoriasis/drug therapy , Sulfonamides/chemistry , Administration, Topical , Animals , Disease Models, Animal , Drug Evaluation, Preclinical , Drug Inverse Agonism , Humans , Inhibitory Concentration 50 , Interleukin-17/metabolism , Interleukin-23/pharmacology , Keratinocytes/cytology , Keratinocytes/drug effects , Keratinocytes/metabolism , Mice , Mice, Inbred BALB C , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Psoriasis/pathology , Skin Diseases/chemically induced , Skin Diseases/drug therapy , Skin Diseases/pathology , Structure-Activity Relationship , Sulfonamides/metabolism , Sulfonamides/therapeutic use , Th17 Cells/cytology , Th17 Cells/drug effects , Th17 Cells/metabolismABSTRACT
Virtual fragmentation of a library of 12,000 compounds inspired by natural products led to a dataset of 153,000 fragments that was used as a source to identify effective P2-P3 scaffold replacement solutions for peptidic Caspase-1 inhibitors. Our strategy led to the identification of an original 2-azabicyclo-octane scaffold (2-ABO) that was further elaborated into the potent Caspase-1 inhibitor CD10847 (IC50â¯=â¯17â¯nM). The crystal structure of Caspase-1 in complex with CD10847 was obtained, and its binding mode was shown to be similar to the one predicted by docking and in good agreement with other known inhibitors.
Subject(s)
4-Butyrolactone/analogs & derivatives , Caspase 1/chemistry , Caspase Inhibitors/chemistry , Dipeptides/chemistry , 4-Butyrolactone/chemical synthesis , 4-Butyrolactone/chemistry , 4-Butyrolactone/metabolism , Azabicyclo Compounds/chemistry , Azabicyclo Compounds/metabolism , Binding Sites , Biological Products/chemistry , Biological Products/metabolism , Caspase 1/metabolism , Caspase Inhibitors/metabolism , Crystallography, X-Ray , Dipeptides/chemical synthesis , Dipeptides/metabolism , Hydrogen Bonding , Inhibitory Concentration 50 , Molecular Conformation , Molecular Docking Simulation , Protein Structure, TertiaryABSTRACT
Targeting the IL17 pathway and more specifically the nuclear receptor RORγ is thought to be beneficial in multiple skin disorders. The Letter describes the discovery of phenoxyindazoles and thiophenoxy indazoles as potent RORγ inverse agonists. Optimization of the potency and efforts to mitigate the phototoxic liability of the series are presented. Finally, crystallization of the lead compound revealed that the series bound to an allosteric site of the nuclear receptor. Such compounds could be useful as tool compounds for understanding the impact of topical treatment on skin disease models.
