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
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
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.
Subject(s)
Indazoles/chemistry , Indazoles/pharmacology , Nuclear Receptor Subfamily 1, Group F, Member 3/agonists , Drug Inverse Agonism , Humans , Molecular Docking Simulation , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Structure-Activity RelationshipABSTRACT
Quer estimular o leitor a privilegiar uma atitude reflexiva em relação ao conhecimento médico, adotando uma perspectiva crítica, não meramente histórica, mas igualmente epistemológica. Apanhado cronológico com relatos sobre as conquistas determinantes da Medicina, a evolução de suas grandes opções teóricas e de suas metodologias de investigação. Através de quatro estudos de caso se apresentam e cruzam instrumentos de análise histórica, da filosofia e da sociologia das ciências, a fim de mostrar o entrelaçamento das lógicas inerentes aos procedimentos adotados por médicos e pesquisadores no decorrer dos séculos.
