Abstract
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.
Keywords:
Aminonitrile synthesis; Polymorph; Psoriasis; Solubility; TACE inhibitor.
Copyright © 2017. Published by Elsevier Ltd.
MeSH terms
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ADAM17 Protein / antagonists & inhibitors*
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ADAM17 Protein / metabolism
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Administration, Topical
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Animals
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Drug Design
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / therapeutic use
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Female
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Humans
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Hydroxamic Acids / chemistry
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Mice
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Mice, Hairless
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Microsomes, Liver / metabolism
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Oxazolone / toxicity
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Psoriasis / drug therapy
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Psoriasis / pathology
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Skin Diseases / chemically induced
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Skin Diseases / prevention & control
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Skin Diseases / veterinary
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Solubility
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Sulfonamides / chemical synthesis
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Sulfonamides / chemistry
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Sulfonamides / therapeutic use
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Enzyme Inhibitors
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Hydroxamic Acids
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Sulfonamides
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Tumor Necrosis Factor-alpha
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Oxazolone
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ADAM17 Protein