Novel tricyclic inhibitors of IKK2: Discovery and SAR leading to the identification of 2-methoxy-N-((6-(1-methyl-4-(methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl)acetamide (BMS-066)

Scott H. Watterson; Charles M. Langevine; Katy Van Kirk; James Kempson; Junquing Guo; Steven H. Spergel; Jagabandhu Das; Robert V. Moquin; Alaric J. Dyckman; David Nirschl; Kurt Gregor; Mark A. Pattoli; Xiaoxia Yang; Kim W. McIntyre; Guchen Yang; Michael A. Galella; Hollie Booth-Lute; Laishun Chen; Zheng Yang; David Wang-Iverson; Murray McKinnon; John H. Dodd; Joel C. Barrish; James R. Burke; William J. Pitts

doi:10.1016/j.bmcl.2011.09.111

Novel tricyclic inhibitors of IKK2: Discovery and SAR leading to the identification of 2-methoxy-N-((6-(1-methyl-4-(methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl)acetamide (BMS-066)

Scott H. Watterson, Charles M. Langevine, Katy Van Kirk, James Kempson, Junquing Guo, Steven H. Spergel, Jagabandhu Das, Robert V. Moquin, Alaric J. Dyckman, David Nirschl, Kurt Gregor, Mark A. Pattoli, Xiaoxia Yang, Kim W. McIntyre, Guchen Yang, Michael A. Galella, Hollie Booth-Lute, Laishun Chen, Zheng Yang, David Wang-IversonMurray McKinnon, John H. Dodd, Joel C. Barrish, James R. Burke, William J. Pitts

Chemistry

Research output: Contribution to journal › Article › peer-review

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Abstract

The synthesis, structure-activity relationships (SAR), and biological results of pyridyl-substituted azaindole based tricyclic inhibitors of IKK2 are described. Compound 4m demonstrated potent in vitro potency, acceptable pharmacokinetic and physicochemical properties, and efficacy when dosed orally in a mouse model of inflammatory bowel disease.

Original language	English (US)
Pages (from-to)	7006-7012
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	23
DOIs	https://doi.org/10.1016/j.bmcl.2011.09.111
State	Published - Dec 1 2011

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2011.09.111

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Watterson, S. H., Langevine, C. M., Van Kirk, K., Kempson, J., Guo, J., Spergel, S. H., Das, J., Moquin, R. V., Dyckman, A. J., Nirschl, D., Gregor, K., Pattoli, M. A., Yang, X., McIntyre, K. W., Yang, G., Galella, M. A., Booth-Lute, H., Chen, L., Yang, Z., ... Pitts, W. J. (2011). Novel tricyclic inhibitors of IKK2: Discovery and SAR leading to the identification of 2-methoxy-N-((6-(1-methyl-4-(methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl)acetamide (BMS-066). Bioorganic and Medicinal Chemistry Letters, 21(23), 7006-7012. https://doi.org/10.1016/j.bmcl.2011.09.111

Watterson, Scott H. ; Langevine, Charles M. ; Van Kirk, Katy et al. / Novel tricyclic inhibitors of IKK2 : Discovery and SAR leading to the identification of 2-methoxy-N-((6-(1-methyl-4-(methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl)acetamide (BMS-066). In: Bioorganic and Medicinal Chemistry Letters. 2011 ; Vol. 21, No. 23. pp. 7006-7012.

@article{b35ee7a1a3064efab0082409f0737857,

title = "Novel tricyclic inhibitors of IKK2: Discovery and SAR leading to the identification of 2-methoxy-N-((6-(1-methyl-4-(methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl)acetamide (BMS-066)",

abstract = "The synthesis, structure-activity relationships (SAR), and biological results of pyridyl-substituted azaindole based tricyclic inhibitors of IKK2 are described. Compound 4m demonstrated potent in vitro potency, acceptable pharmacokinetic and physicochemical properties, and efficacy when dosed orally in a mouse model of inflammatory bowel disease.",

author = "Watterson, {Scott H.} and Langevine, {Charles M.} and {Van Kirk}, Katy and James Kempson and Junquing Guo and Spergel, {Steven H.} and Jagabandhu Das and Moquin, {Robert V.} and Dyckman, {Alaric J.} and David Nirschl and Kurt Gregor and Pattoli, {Mark A.} and Xiaoxia Yang and McIntyre, {Kim W.} and Guchen Yang and Galella, {Michael A.} and Hollie Booth-Lute and Laishun Chen and Zheng Yang and David Wang-Iverson and Murray McKinnon and Dodd, {John H.} and Barrish, {Joel C.} and Burke, {James R.} and Pitts, {William J.}",

year = "2011",

month = dec,

day = "1",

doi = "10.1016/j.bmcl.2011.09.111",

language = "English (US)",

volume = "21",

pages = "7006--7012",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Limited",

number = "23",

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Watterson, SH, Langevine, CM, Van Kirk, K, Kempson, J, Guo, J, Spergel, SH, Das, J, Moquin, RV, Dyckman, AJ, Nirschl, D, Gregor, K, Pattoli, MA, Yang, X, McIntyre, KW, Yang, G, Galella, MA, Booth-Lute, H, Chen, L, Yang, Z, Wang-Iverson, D, McKinnon, M, Dodd, JH, Barrish, JC, Burke, JR & Pitts, WJ 2011, 'Novel tricyclic inhibitors of IKK2: Discovery and SAR leading to the identification of 2-methoxy-N-((6-(1-methyl-4-(methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl)acetamide (BMS-066)', Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 23, pp. 7006-7012. https://doi.org/10.1016/j.bmcl.2011.09.111

Novel tricyclic inhibitors of IKK2: Discovery and SAR leading to the identification of 2-methoxy-N-((6-(1-methyl-4-(methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl)acetamide (BMS-066). / Watterson, Scott H.; Langevine, Charles M.; Van Kirk, Katy et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 21, No. 23, 01.12.2011, p. 7006-7012.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Novel tricyclic inhibitors of IKK2

T2 - Discovery and SAR leading to the identification of 2-methoxy-N-((6-(1-methyl-4-(methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl)acetamide (BMS-066)

AU - Watterson, Scott H.

AU - Langevine, Charles M.

AU - Van Kirk, Katy

AU - Kempson, James

AU - Guo, Junquing

AU - Spergel, Steven H.

AU - Das, Jagabandhu

AU - Moquin, Robert V.

AU - Dyckman, Alaric J.

AU - Nirschl, David

AU - Gregor, Kurt

AU - Pattoli, Mark A.

AU - Yang, Xiaoxia

AU - McIntyre, Kim W.

AU - Yang, Guchen

AU - Galella, Michael A.

AU - Booth-Lute, Hollie

AU - Chen, Laishun

AU - Yang, Zheng

AU - Wang-Iverson, David

AU - McKinnon, Murray

AU - Dodd, John H.

AU - Barrish, Joel C.

AU - Burke, James R.

AU - Pitts, William J.

PY - 2011/12/1

Y1 - 2011/12/1

N2 - The synthesis, structure-activity relationships (SAR), and biological results of pyridyl-substituted azaindole based tricyclic inhibitors of IKK2 are described. Compound 4m demonstrated potent in vitro potency, acceptable pharmacokinetic and physicochemical properties, and efficacy when dosed orally in a mouse model of inflammatory bowel disease.

AB - The synthesis, structure-activity relationships (SAR), and biological results of pyridyl-substituted azaindole based tricyclic inhibitors of IKK2 are described. Compound 4m demonstrated potent in vitro potency, acceptable pharmacokinetic and physicochemical properties, and efficacy when dosed orally in a mouse model of inflammatory bowel disease.

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U2 - 10.1016/j.bmcl.2011.09.111

DO - 10.1016/j.bmcl.2011.09.111

M3 - Article

C2 - 22018461

AN - SCOPUS:80255129403

SN - 0960-894X

VL - 21

SP - 7006

EP - 7012

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 23

ER -

Watterson SH, Langevine CM, Van Kirk K, Kempson J, Guo J, Spergel SH et al. Novel tricyclic inhibitors of IKK2: Discovery and SAR leading to the identification of 2-methoxy-N-((6-(1-methyl-4-(methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl)acetamide (BMS-066). Bioorganic and Medicinal Chemistry Letters. 2011 Dec 1;21(23):7006-7012. doi: 10.1016/j.bmcl.2011.09.111

Novel tricyclic inhibitors of IKK2: Discovery and SAR leading to the identification of 2-methoxy-N-((6-(1-methyl-4-(methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl)acetamide (BMS-066)

Abstract

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