A novel series of IKKβ inhibitors part II: Description of a potent and pharmacologically active series of analogs

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 1, 2011, Pages 423-426

  Cushing, Timothy D ^a   Baichwal, Vijay ^a   Berry, Karen ^a   Billedeau, Roland ^b   Bordunov, Viola ^b   Broka, Chris ^b   Browner, Michelle F ^d   Cardozo, Mario ^a   Cheng, Peng ^a   Clark, David ^a   Dalrymple, Stacie ^c   Degraffenreid, Michael ^a   Gill, Adrian ^b   Hao, Xiaolin ^a   Hawley, Ronald C ^b   He, Xiao ^a   Labadie, Sharada S ^b   Labelle, Marc ^a   Lehel, Csaba ^a   Lu, Pu Ping ^a   McIntosh, Joel ^b   Miao, Shichang ^a   Parast, Camran ^a   Shin, Youngsook ^a   Sjogren, Eric B ^b   Smith, Marie Louise ^a   Talamas, Francisco X ^b   Tonn, George ^a   Walker, Keith M ^b   Walker, Nigel P C ^a   Wesche, Holger ^a   Whitehead, Chris ^b   Wright, Matt ^a   Jaen, Juan C ^a   more..

^a AMGEN INC   (United States)

^b Chemistry   (United States)

^c Molecular Biology   (United States)

^d Discovery Technologies   (United States)

Author keywords

Arthritis; Collagen; IKK ; IKK ; Semithiocarbazones

Indexed keywords

1 [[2 (1 METHYL IH IMIDAZOL 5 YL)QUINOLIN 4 YL]METHYLENE]THIOSEMICARBAZIDE; 6 CYANOETHYL 7 CHLOROQUINOLINE; I KAPPA B KINASE BETA; PROTEIN SERINE THREONINE KINASE INHIBITOR; THIOSEMICARBAZIDE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG POTENCY; DRUG SYNTHESIS; ENTERITIS; HUMAN; HUMAN CELL; IC 50; MAXIMUM PLASMA CONCENTRATION; MOUSE; NONHUMAN; PHYSICAL CHEMISTRY; STRUCTURE ACTIVITY RELATION;

ANIMALS; DOGS; FEMALE; HEPATOCYTES; HIGH-THROUGHPUT SCREENING ASSAYS; HUMANS; I-KAPPA B KINASE; MACACA MULATTA; MALE; MICE; PROTEIN KINASE INHIBITORS; QUINOLINES; RATS; SEMICARBAZIDES; STRUCTURE-ACTIVITY RELATIONSHIP; THIOUREA;

EID: 78650516396     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.10.125     Document Type: Article

References (10)

1. See T.D. Cushing, V. Baichwal, K. Berry, R. Billedeau, V. Bordunov, C. Broka, M. Cardozo, P. Cheng, D. Clark, S. Dalrymple, M. DeGraffenreid, G. Gill, X. Hao, R.C. Hawley, X. He, J.C. Jaen, S.S. Labadie, M. Labelle, C. Lehel, P.-P. Lu, J. McIntosh, S. Miao, C. Parast, Y. Shin, E.B. Sjogren, M.-L. Smith, F.X. Talamas, G. Tonn, K.M. Walker, N.C.P. Walker, H. Wesche, C. Whitehead, M. Wright, and M.F. Browner Bioorg. Med. Chem. Lett. 21 2010 417 for details pertaining to the assays, synthesis and initial SAR
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7. BALB/C mice were treated with compound 2 (PO) at various doses, followed by IP delivery of LPS in 0.5 h. Mice were bled 1.5 h later and their blood plasma analyzed for TNFα levels by ELISA.
8. Collagen/CFA was delivered subcutaneously at day zero, followed by LPS (50 mg, IP) stimulation on day 21. On day 22, compound 2 (100 mg/kg) in a HPMC vehicle was administered orally (QD) until day 35. The study was blinded with respect to treatment. Mean clinical score (MCS) was based on observed edema, erythema and severe joint damage.
9. 2O thereafter. The compound 2 was dosed at 25 mg/kg and 10 mg/kg orally (BID) from day 0 until day 9. At sacrifice (day 10) the 3 mm colon tissues biopsy was incubated for 24 h and the resulting supernatant assayed for TNFα and IL-1B via ELISA. The colons were clinically scored and tissues evaluated histopathologically.
10. 6 Cells. {[HSA (human serum albumin)] = 40 mg/mL, [AAG (α1-acid glycoprotein) = 2 mg/mL]}.