65012-14-8Relevant academic research and scientific papers
Identification, Synthesis, and Biological Evaluation of the Major Human Metabolite of NLRP3 Inflammasome Inhibitor MCC950
Salla, Manohar,Butler, Mark S.,Pelingon, Ruby,Kaeslin, Geraldine,Croker, Daniel E.,Reid, Janet C.,Baek, Jong Min,Bernhardt, Paul V.,Gillam, Elizabeth M. J.,Cooper, Matthew A.,Robertson, Avril A. B.
, p. 1034 - 1038 (2016)
MCC950 is an orally bioavailable small molecule inhibitor of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome that exhibits remarkable activity in multiple models of inflammatory disease. Incubation of MCC950 with human liver microsomes, and subsequent analysis by HPLC-MS/MS, revealed a major metabolite, where hydroxylation of MCC950 had occurred on the 1,2,3,5,6,7-hexahydro-s-indacene moiety. Three possible regioisomers were synthesized, and coelution using HPLC-MS/MS confirmed the structure of the metabolite. Further synthesis of individual enantiomers and coelution studies using a chiral column in HPLC-MS/MS showed the metabolite was R-(+)- N-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide (2a). Incubation of MCC950 with a panel of cytochrome P450 enzymes showed P450s 2A6, 2C9, 2C18, 2C19, 2J2, and 3A4 catalyze the formation of the major metabolite 2a, with a lower level of activity shown by P450s 1A2 and 2B6. All of the synthesized compounds were tested for inhibition of NLRP3-induced production of the pro-inflammatory cytokine IL-1β from human monocyte derived macrophages. The identified metabolite 2a was 170-fold less potent than MCC950, while one regioisomer had nanomolar inhibitory activity. These findings also give first insight into the SAR of the hexahydroindacene moiety.
COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH NLRP ACTIVITY
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Page/Page column 280-281, (2020/06/05)
In one aspect, compounds of Formula AA, or a pharmaceutically acceptable salt thereof, are featured or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula A can be as defined anywhere herein.
SULFONIMIDAMIDE COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH NLRP ACTIVITY
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Page/Page column 472-473, (2020/08/13)
In one aspect, compounds of Formula AA, or a pharmaceutically acceptable salt thereof, are featured: (Formula AA) or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula A can be as defined anywhere herein.
COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH NLRP ACTIVITY
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Page/Page column 461; 462, (2019/02/13)
In one aspect, compounds of Formula AA, or a pharmaceutically acceptable salt thereof, are featured.The variables shown in Formula AA are as defined in the claims. The compounds of formula AA are NLRP3 activity modulators and, as such, can be used in the treatment of metabolic disorders (e.g. Type 2 diabetes, atherosclerosis, obesity or gout), a disease of the central nervous system (e.g. Alzheimer's disease, multiple sclerosis, Amyotrophic Lateral Sclerosis or Parkinson's disease), lung disease (e.g. asthma, COPD or pulmonary idiopathic fibrosis), liver disease (e.g. NASH syndrome, viral hepatitis or cirrhosis), pancreatic disease (e.g. acute pancreatitis or chronic pancreatitis), kidney disease (e.g. acute kidney injury or chronic kidney injury), intestinal disease (e.g. Crohn's disease or Ulcerative Colitis), skin disease (e.g. psoriasis), musculoskeletal disease (e.g. scleroderma), a vessel disorder (e.g. giant cell arteritis), a disorder of the bones (e.g. osteoarthritis, osteoporosis or osteopetrosis disorders), eye disease (e.g. glaucoma or macular degeneration), a disease caused by viral infection (e.g. HIV or AIDS), an autoimmune disease (e.g. Rheumatoid Arthritis, Systemic Lupus Erythematosus or Autoimmune Thyroiditis), cancer or aging.
Regioselectivity of acid-catalyzed cyclization of 1-(3,4-dialkylaryl)-3- chloropropan-1-ones to indanones. Comparison of experimental data and results of computer simulation
Ivchenko,Nifant'Ev,Ustynyuk,Ezerskii
experimental part, p. 929 - 935 (2010/10/04)
The acid-catalyzed cyclization of 1-(3,4-dialkylaryl)-3-chloropropan-1-ones to dialkyl-indanones via the intermediate formation of (3,4-dialkylaryl) propenones was studied. This reaction affords isomeric products: 5,6-dialkylindan-1-ones and 4,5-dialkylin
Novel synthesis of 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl) furan-2-sulfonyl]urea, An anti-inflammatory agent
Urban, Frank J.,Jasys, V. John,Raggon, Jeffrey W.,Buzon, Richard A.,Hill, Paul D.,Eggler, James F.,Weaver, John D.
, p. 2029 - 2043 (2007/10/03)
A novel synthesis of the anti-inflammatory agent 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)- furan-2-sulfonyl]urea 1 is described. Sulfonamide 5 was prepared starting from ethyl 3-furoate 2. Key steps were a one-pot sulfonylation with chlorosulfonic acid in methylene chloride followed by pyridinium salt formation and reaction with phosphorus pentachloride to provide ethyl 2-(chlorosulfonyl)-4-furoate 7. This sulfonyl chloride was treated with ammonium bicarbonate to form sulfonamide 8, followed by treatment with excess methyl magnesium chloride to provide 4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide 5. 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene 16 was prepared from indan in five steps. The formation of the desired sulfonyl urea was carried out both with the isolated isocyanate 16 and via an in situ method.
Aromatic Spiranes, XIV: Syntheses of 2,2'-Spirobi-(s-hydrindacene) and its precursors
Neudeck, Horst K.
, p. 627 - 658 (2007/10/02)
The title compound 35 was prepared by catalytic reduction of the diones 29a and 11a. 29a was synthesized by systematic anellation of fivemembered rings to the positions 5,6 and 5',6', resp., of 2,2'-spirobiindane.The preparation of 11a was achieved by Friedel-Crafts cyclisation of bis-(5-indanylmethyl)-malonic acid. s-Hydrindacene-1-one 5a was prepared as a precursor for the synthesis of 11a (see forthcoming publication) and its derivates as models for corresponding anellation and substitution reactions. - Keywords: s-Hydrindacene-1-one and derivates; Mono- and bisanellation; 2,2'-Spirobiindane; 1H-nmr spectra
