ABSTRACT
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
Targeting the TNFα pathway is a validated approach to the treatment of psoriasis. In this pathway, TACE stands out as a druggable target and has been the focus of in-house research programs. In this article, we present the discovery of clinical candidate 26a. Starting from hits plagued with poor solubility or genotoxicity, 26a was identified through thorough multiparameter optimisation. Showing robust in vivo activity in an oxazolone-mediated inflammation model, the compound was selected for development. Following a polymorph screen, the hydrochloride salt was selected and the synthesis was efficiently developed to yield the API in 47% overall yield.
Subject(s)
ADAM17 Protein/antagonists & inhibitors , Enzyme Inhibitors/chemistry , ADAM17 Protein/metabolism , Administration, Topical , Animals , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/therapeutic use , Female , Humans , Hydroxamic Acids/chemistry , Mice , Mice, Hairless , Microsomes, Liver/metabolism , Oxazolone/toxicity , Psoriasis/drug therapy , Psoriasis/pathology , Skin Diseases/chemically induced , Skin Diseases/prevention & control , Skin Diseases/veterinary , Solubility , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/therapeutic use , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Targeting the Tumor Necrosis Factor α signalling with antibodies has led to a revolution in the treatment of psoriasis. Locally inhibiting Tumor Necrosis Factor α Converting Enzyme (TACE or ADAM17) could potentially mimic those effects and help treat mild to moderate psoriasis, without the reported side effect of systemic TACE inhibitors. Efforts to identify new TACE inhibitors are presented here. Enzymatic SAR as well as ADME and physico-chemistry data are presented. This study culminated in the identification of potent enzymatic inhibitors. Suboptimal cellular activity of this series is discussed in the context of previously published results.
Subject(s)
ADAM17 Protein/antagonists & inhibitors , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Hydroxamic Acids/administration & dosage , Hydroxamic Acids/chemistry , ADAM17 Protein/metabolism , Administration, Topical , Humans , Psoriasis/drug therapy , Psoriasis/enzymologyABSTRACT
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.
