1000053-98-4Relevant academic research and scientific papers
Discovery of the First Potent, Selective, and Orally Bioavailable Signal Peptide Peptidase-Like 2a (SPPL2a) Inhibitor Displaying Pronounced Immunomodulatory Effects in Vivo
Velcicky, Juraj,Bodendorf, Ursula,Rigollier, Pascal,Epple, Robert,Beisner, Daniel R.,Guerini, Danilo,Smith, Philip,Liu, Bo,Feifel, Roland,Wipfli, Peter,Aichholz, Reiner,Couttet, Philippe,Dix, Ina,Widmer, Toni,Wen, Ben,Brandl, Trixi
, p. 865 - 880 (2018)
Signal peptide peptidase-like 2a (SPPL2a) is an aspartic intramembrane protease which has recently been shown to play an important role in the development and function of antigen presenting cells such as B lymphocytes and dendritic cells. In this paper, we describe the discovery of the first selective and orally active SPPL2a inhibitor (S)-2-cyclopropyl-N1-((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine-2,1′-cyclopropan]-10-yl)-N4-(5-fluoro-2-methylpyridin-3-yl)succinamide 40 (SPL-707). This compound shows adequate selectivity against the closely related enzymes γ-secretase and SPP and a good pharmacokinetic profile in mouse and rat. Compound 40 significantly inhibited processing of the SPPL2a substrate CD74/p8 fragment in rodents at doses ≤10 mg/kg b.i.d. po. Oral dosing of 40 for 11 days at ≥10 mg/kg b.i.d. recapitulated the phenotype seen in Sppl2a knockout (ko) and ENU mutant mice (reduced number of specific B cells and myeloid dendritic cells). Thus, we believe that SPPL2a represents an interesting and druggable pharmacological target, potentially providing a novel approach for the treatment of autoimmune diseases by targeting B cells and dendritic cells.
ANTI-OSTEOARTHRITIS HYDANTOIN COMPOUNDS AND RELATED COMPOSITIONS AND METHODS
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, (2021/02/12)
This invention provides hydantoin compounds that inhibit both aggrecanase 1 (Adamts4) and aggrecanase 2 (Adamts5). This invention also provides related compositions and methods for treating inflammatory diseases, diseases involving degradation of cartilage, and diseases involving the disruption of cartilage homeostasis.
A Highly Selective Hydantoin Inhibitor of Aggrecanase-1 and Aggrecanase-2 with a Low Projected Human Dose
Durham, Timothy B.,Marimuthu, Jothirajah,Toth, James L.,Liu, Chin,Adams, Lisa,Mudra, Daniel R.,Swearingen, Craig,Lin, Chaohua,Chambers, Mark G.,Thirunavukkarasu, Kannan,Wiley, Michael R.
, p. 5933 - 5939 (2017/07/22)
Aggrecanase-1 and -2 (ADAMTS-4 and ADAMTS-5) are zinc metalloproteases involved in the degradation of aggrecan in cartilage. Inhibitors could provide a means of altering the progression of osteoarthritis. We report the identification of 7 which had good oral pharmacokinetics in rats and showed efficacy in a rat chemical model of osteoarthritis. The projected human dose required to achieve sustained plasma levels ≥10 times the hADAMTS-5 IC50 is 5 mg q.d.
MACROCYCLIC INHIBITORS OF FLAVIVIRIDAE VIRUSES
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Page/Page column 302; 303, (2014/01/08)
Provided are compounds of Formula I and pharmaceutically acceptable salts and esters thereof. The compounds, compositions, and methods provided are useful for the treatment of virus infections, particularly hepatitis C infections.
Electron-transfer photoredox catalysis: Development of a tin-free reductive dehalogenation reaction
Narayanam, Jagan M. R.,Tucker, Joseph W.,Stephenson, Corey R. J.
supporting information; experimental part, p. 8756 - 8757 (2009/12/04)
(Chemical Equation Presented) We report an operationally simple, tin-free reductive dehalogenation system utilizing the well-known visible-light-activated photoredox catalyst Ru(bpy)3Cl2 in combination with iPr2
CYCLIC AMINE COMPOUND
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Page/Page column 150, (2009/04/23)
The present invention provides an excellent antihypertensive medicament. The medicament of the present invention comprises a compound having the general formula (I) and the like: [wherein R1: H, substitutable alkyl, substitutable alkenyl, substitutable cyclic hydrocarbon, substitutable heterocyclyl or the like; R2: H, substitutable alkyl, substitutable alkenyl, substitutable cycloalkyl or the like; R3, R4; H, substitutable alkyl, substitutable alkenyl, substitutable cycloalkyl or the like; R5, R6: H, substitutable alkyl, substitutable cycloalkyl, substitutable alkoxy or the like; R7, R8: H, substitutable alkyl, substitutable cycloalkyl or the like; X: the formula (II) or the like; A: substitutable cyclic hydrocarbon, substitutable heterocyclyl or the like; Y: a single bond, substitutable alkylene, substitutable alkenylene, -(CH2)a-X1-(CH2)b- (X1: the formula -NH-, -O- or the like; a, b: 0-5) or the like; B: substitutable cyclic hydrocarbon, substitutable heterocyclyl or the like].
