Discovery of a series of ester-substituted NLRP3 inflammasome inhibitors.

Autor: Harrison D; NodThera Ltd., Suite 8, The Mansion, Chesterford Research Park, Little Chesterford, Saffron Walden, Essex CB10 1XL, United Kingdom. Electronic address: david.harrison@nodthera.com., Boutard N; Selvita S.A. (now Ryvu Therapeutics), Park Life Science, ul. Bobrzynskiego 14, 30-348, Kraków, Poland., Brzozka K; Selvita S.A. (now Ryvu Therapeutics), Park Life Science, ul. Bobrzynskiego 14, 30-348, Kraków, Poland., Bugaj M; Selvita S.A. (now Ryvu Therapeutics), Park Life Science, ul. Bobrzynskiego 14, 30-348, Kraków, Poland., Chmielewski S; Selvita S.A. (now Ryvu Therapeutics), Park Life Science, ul. Bobrzynskiego 14, 30-348, Kraków, Poland., Cierpich A; Selvita S.A. (now Ryvu Therapeutics), Park Life Science, ul. Bobrzynskiego 14, 30-348, Kraków, Poland., Doedens JR; NodThera Inc., 454 N 34(th) Street, Seattle, WA 98103, USA., Fabritius CRY; Selvita S.A. (now Ryvu Therapeutics), Park Life Science, ul. Bobrzynskiego 14, 30-348, Kraków, Poland., Gabel CA; NodThera Inc., 454 N 34(th) Street, Seattle, WA 98103, USA., Galezowski M; Selvita S.A. (now Ryvu Therapeutics), Park Life Science, ul. Bobrzynskiego 14, 30-348, Kraków, Poland., Kowalczyk P; Selvita S.A. (now Ryvu Therapeutics), Park Life Science, ul. Bobrzynskiego 14, 30-348, Kraków, Poland., Levenets O; Selvita S.A. (now Ryvu Therapeutics), Park Life Science, ul. Bobrzynskiego 14, 30-348, Kraków, Poland., Mroczkowska M; Selvita S.A. (now Ryvu Therapeutics), Park Life Science, ul. Bobrzynskiego 14, 30-348, Kraków, Poland., Palica K; Selvita S.A. (now Ryvu Therapeutics), Park Life Science, ul. Bobrzynskiego 14, 30-348, Kraków, Poland., Porter RA; Rod Porter Consultancy, 89 Back Street, Ashwell, Baldock, Hertfordshire SG7 5PG, United Kingdom., Schultz D; Selvita S.A. (now Ryvu Therapeutics), Park Life Science, ul. Bobrzynskiego 14, 30-348, Kraków, Poland., Sowinska M; Selvita S.A. (now Ryvu Therapeutics), Park Life Science, ul. Bobrzynskiego 14, 30-348, Kraków, Poland., Topolnicki G; Selvita S.A. (now Ryvu Therapeutics), Park Life Science, ul. Bobrzynskiego 14, 30-348, Kraków, Poland., Urbanski P; Selvita S.A. (now Ryvu Therapeutics), Park Life Science, ul. Bobrzynskiego 14, 30-348, Kraków, Poland., Woyciechowski J; Selvita S.A. (now Ryvu Therapeutics), Park Life Science, ul. Bobrzynskiego 14, 30-348, Kraków, Poland., Watt AP; NodThera Ltd., Suite 8, The Mansion, Chesterford Research Park, Little Chesterford, Saffron Walden, Essex CB10 1XL, United Kingdom.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2020 Dec 01; Vol. 30 (23), pp. 127560. Date of Electronic Publication: 2020 Sep 18.
DOI: 10.1016/j.bmcl.2020.127560
Abstrakt: The NLRP3 inflammasome is a component of the innate immune system involved in the production of proinflammatory cytokines. Aberrant activation by a wide range of exogenous and endogenous signals can lead to chronic, low-grade inflammation. It has attracted a great deal of interest as a drug target due to the association with diseases of large unmet medical need such as Alzheimer's disease, Parkinson's disease, arthritis, and cancer. To date, no drugs specifically targeting inhibition of the NLRP3 inflammasome have been approved. In this work, we used the known NLRP3 inflammasome inhibitor CP-456,773 (aka CRID3 or MCC 950) as our starting point and undertook a Structure-Activity Relationship (SAR) analysis and subsequent scaffold-hopping exercise. This resulted in the rational design of a series of novel ester-substituted urea compounds that are highly potent and selective NLRP3 inflammasome inhibitors, as exemplified by compounds 44 and 45. It is hypothesized that the ester moiety acts as a highly permeable delivery vehicle and is subsequently hydrolyzed to the carboxylic acid active species by carboxylesterase enzymes. These molecules are greatly differentiated from the state-of-the-art and offer potential in the treatment of NLRP3-driven diseases, particularly where tissue penetration is required.
(Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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