1002359-91-2Relevant academic research and scientific papers
Design, synthesis and biological evaluation of 7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives as selective Btk inhibitors with improved pharmacokinetic properties for the treatment of rheumatoid arthritis
He, Linhong,Pei, Heying,Zhang, Chufeng,Shao, Mingfeng,Li, Dan,Tang, Mingli,Wang, Taijing,Chen, Xiaoxin,Xiang, Mingli,Chen, Lijuan
, p. 96 - 112 (2018)
Bruton's tyrosine kinase (Btk) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) and Fcγ receptor (FcR) signaling pathways, which makes it a uniquely attractive target for the treatment of autoimmune diseases, such as rheumatoid arthritis (RA). We reported a series of compounds bearing 7H-pyrrolo [2,3-d]pyrimidin-4-amine scaffold that potently inhibited Btk in vitro. Analysis of the structure-activity relationships (SAR) and drug-like profiles led to the discovery of the optimal compound B16. B16 preferentially inhibited Btk (IC50 = 21.70 ± 0.82 nM) over closely related kinases with moderate selectivity. Cell-based tests also confirmed that B16 significantly inhibited Btk Y223 auto-phosphorylation and PLCγ2 Y1217 phosphorylation. MTT revealed that B16 displayed weak suppression against normal LO2, HEK293 and THP-1 cell lines with IC50 values over 30 μM. Moreover, B16 showed very weak potential to block the hERG channel (IC50 = 11.10 μM) in comparison to ibrutinib (IC50 = 0.97 μM). Owing to its favorable physicochemical properties (ClogP = 2.53, aqueous solubility ≈ 0.1 mg/mL), pharmacokinetic profiles (F = 49.15%, t1/2 = 7.02 h) and reasonable CYP450 profile, B16 exhibited potent anti-arthritis activity and similar efficacy to ibrutinib in reducing paw thickness in CIA mice. In conclusion, B16 is a potent, selective and durable inhibitor of Btk and has the potential to a safe and efficacious treatment for arthritis.
Identification of 2,4-Disubstituted Imidazopyridines as Hemozoin Formation Inhibitors with Fast-Killing Kinetics and in Vivo Efficacy in the Plasmodium falciparum NSG Mouse Model
Horatscheck, André,Andrijevic, Ana,Nchinda, Aloysius T.,Le Manach, Claire,Paquet, Tanya,Khonde, Lutete Peguy,Dam, Jean,Pawar, Kailash,Taylor, Dale,Lawrence, Nina,Brunschwig, Christel,Gibhard, Liezl,Njoroge, Mathew,Reader, Janette,Van Der Watt, Mari?tte,Wicht, Kathryn,De Sousa, Ana Carolina C.,Okombo, John,Maepa, Keletso,Egan, Timothy J.,Birkholtz, Lyn-Marie,Basarab, Gregory S.,Wittlin, Sergio,Fish, Paul V.,Street, Leslie J.,Duffy, James,Chibale, Kelly
supporting information, p. 13013 - 13030 (2020/11/13)
A series of 2,4-disubstituted imidazopyridines, originating from a SoftFocus Kinase library, was identified from a high throughput phenotypic screen against the human malaria parasite Plasmodium falciparum. Hit compounds showed moderate asexual blood stage activity. During lead optimization, several issues were flagged such as cross-resistance against the multidrug-resistant K1 strain, in vitro cytotoxicity, and cardiotoxicity and were addressed through structure-Activity and structure-property relationship studies. Pharmacokinetic properties were assessed in mice for compounds showing desirable in vitro activity, a selectivity window over cytotoxicity, and microsomal metabolic stability. Frontrunner compound 37 showed good exposure in mice combined with good in vitro activity against the malaria parasite, which translated into in vivo efficacy in the P. falciparum NOD-scid IL-2Rnull (NSG) mouse model. Preliminary mechanistic studies suggest inhibition of hemozoin formation as a contributing mode of action.
NOVEL ADENINE DERIVATIVES
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Page/Page column 58, (2010/04/03)
Compounds of formula (I) wherein R1 is C1-6alkylamino, or C1-6alkoxy; R2 is a group having the structure (II): n is an integer having a value of 1 to 6; Het is a 6-membered saturated heterocycle containing one nitrogen atom wherein Het is attached to the -(CH2)n- moiety at any carbon atom of the heterocycle; R3 is hydrogen, C1-8alkyl, or C3-7cycloalkylC0-6alkyl; and salts thereof are inducers of human interferon. Compounds which induce human interferon may be useful in the treatment of various disorders, for example the treatment of allergic diseases and other inflammatory conditions for example allergic rhinitis and asthma, the treatment of infectious diseases and cancer, and may also be useful as vaccine adjuvants.
Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3- piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase
Heerding, Dirk A.,Rhodes, Nelson,Leber, Jack D.,Clark, Tammy J.,Keenan, Richard M.,Lafrance, Louis V.,Li, Mei,Safonov, Igor G.,Takata, Dennis T.,Venslavsky, Joseph W.,Yamashita, Dennis S.,Choudhry, Anthony E.,Copeland, Robert A.,Lai, Zhihong,Schaber, Michael D.,Tummino, Peter J.,Strum, Susan L.,Wood, Edgar R.,Duckett, Derek R.,Eberwein, Derek,Knick, Victoria B.,Lansing, Timothy J.,McConnell, Randy T.,Zhang, ShuYun,Minthorn, Elisabeth A.,Concha, Nestor O.,Warren, Gregory L.,Kumar, Rakesh
experimental part, p. 5663 - 5679 (2009/08/07)
Overexpression of AKT has an antiapoptotic effect in many cell types, and expression of dominant negative AKT blocks the ability of a variety of growth factors to promote survival. Therefore, inhibitors of AKT kinase activity might be useful as monotherapy for the treatment of tumors with activated AKT. Herein, we describe our lead optimization studies culminating in the discovery of compound 3g (GSK690693). Compound 3g is a novel ATP competitive, pan-AKT kinase inhibitor with IC50 values of 2, 13, and 9 nM against AKT1, 2, and 3, respectively. An X-ray cocrystal structure was solved with 3g and the kinase domain of AKT2, confirming that 3g bound in the ATP binding pocket. Compound 3g potently inhibits intracellular AKT activity as measured by the inhibition of the phosphorylation levels of GSK3β. Intraperitoneal administration of 3g in immunocompromised mice results in the inhibition of GSK3β phosphorylation and tumor growth in human breast carcinoma (BT474) xenografts.
