Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 29, Issue 12, Pages 1497-1501Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2019.04.014
Keywords
RIPK1; RIPK1 inhibitor; Necroptosis; Metabolic stability; Pentafluoroethyl
Categories
Funding
- Genentech Discovery Chemistry Analytical and Purifications group
- Genentech Compound Management group
- Genentech Protein Chemistry group
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Receptor-interacting protein kinase 1 (RIPK1), a key component of the cellular necroptosis pathway, has gained recognition as an important therapeutic target. Pharmacologic inhibition or genetic inactivation of RIPK1 has shown promise in animal models of disease ranging from acute ischemic conditions, chronic inflammation, and neurodegeneration. We present here a class of RIPK1 inhibitors that is distinguished by a lack of a lipophilic aromatic group present in most literature inhibitors that typically occupies a hydrophobic back pocket of the protein active site. Despite not having this ubiquitous feature of many known RIPK1 inhibitors, we were able to obtain compounds with good potency, kinase selectivity, and pharmacokinetic properties in rats. The use of the lipophilic yet metabolically stable pentafluoroethyl group was critical to balancing the potency and properties of optimized analogs.
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