ABSTRACT
In our hands, efficient access to the 4-amino-3-carboxamide disubstituted pyridine-2(1H)-one kinase hinge-binder motif proved to be more challenging than anticipated requiring a significant investment in route scouting and optimization. This full paper focuses on the synthesis issues that we encountered during our route exploration and the original solutions we found that helped us to identify two optimized library-style processes to prepare our large kinase inhibitor library.
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
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
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.
