The discovery of orally active triaminotriazine aniline amides as inhibitors of p38 MAP kinase

Katerina Leftheris; Gulzar Ahmed; Ran Chan; Alaric J. Dyckman; Zahid Hussain; Kan Ho; John Hynes; Jeffrey Letourneau; Wei Li; Shuqun Lin; Axel Metzger; Kevin J. Moriarty; Chris Riviello; Yvonne Shimshock; James Wen; John Wityak; Stephen T. Wrobleski; Hong Wu; Junjun Wu; Madhuri Desai; Kathleen M. Gillooly; Tsung H. Lin; Derek Loo; Kim W. McIntyre; Sidney Pitt; Ding Ren Shen; David J. Shuster; Rosemary Zhang; David Diller; Arthur Doweyko; John Sack; Jack Baldwin; Joel Barrish; John Dodd; Ian Henderson; Steve Kanner; Gary L. Schieven; Maria Webb

doi:10.1021/jm049521d

The discovery of orally active triaminotriazine aniline amides as inhibitors of p38 MAP kinase

Katerina Leftheris, Gulzar Ahmed, Ran Chan, Alaric J. Dyckman, Zahid Hussain, Kan Ho, John Hynes, Jeffrey Letourneau, Wei Li, Shuqun Lin, Axel Metzger, Kevin J. Moriarty, Chris Riviello, Yvonne Shimshock, James Wen, John Wityak, Stephen T. Wrobleski, Hong Wu, Junjun Wu, Madhuri DesaiKathleen M. Gillooly, Tsung H. Lin, Derek Loo, Kim W. McIntyre, Sidney Pitt, Ding Ren Shen, David J. Shuster, Rosemary Zhang, David Diller, Arthur Doweyko, John Sack, Jack Baldwin, Joel Barrish, John Dodd, Ian Henderson, Steve Kanner, Gary L. Schieven, Maria Webb

Chemistry

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

60 Scopus citations

Abstract

A new structural class of triaminotriazine aniline amides possessing potent p38 enzyme activity has been discovered. The initial hit (compound 1a) was identified through screening the Pharmacopeia ECLiPS compound collection. SAR modification led to the identification of a short acting triaminotriazine aniline methoxyamide (compound 1m) possessing in vitro and in vivo oral activity in animal models of acute and chronic inflammatory disease. An X-ray crystal structure of compound 1m in this class, cocrystallized with unactivated p38a protein, indicates that these compounds bind to the ATP binding pocket and possess key H-bonding interactions within a deeper cleft. Hydrogen bonding between one of the triazine nitrogens and the backbone NH of the Met109 residue occurs through a water molecule. The methoxyamide NH and carbonyl oxygen are within H-bonding distance of Glu71 and Asp168.

Original language	English (US)
Pages (from-to)	6283-6291
Number of pages	9
Journal	Journal of Medicinal Chemistry
Volume	47
Issue number	25
DOIs	https://doi.org/10.1021/jm049521d
State	Published - Dec 2 2004

All Science Journal Classification (ASJC) codes

Molecular Medicine
Drug Discovery

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Leftheris, K., Ahmed, G., Chan, R., Dyckman, A. J., Hussain, Z., Ho, K., Hynes, J., Letourneau, J., Li, W., Lin, S., Metzger, A., Moriarty, K. J., Riviello, C., Shimshock, Y., Wen, J., Wityak, J., Wrobleski, S. T., Wu, H., Wu, J., ... Webb, M. (2004). The discovery of orally active triaminotriazine aniline amides as inhibitors of p38 MAP kinase. Journal of Medicinal Chemistry, 47(25), 6283-6291. https://doi.org/10.1021/jm049521d

@article{a1c1006e2ddc42288f738012317b78bc,

title = "The discovery of orally active triaminotriazine aniline amides as inhibitors of p38 MAP kinase",

abstract = "A new structural class of triaminotriazine aniline amides possessing potent p38 enzyme activity has been discovered. The initial hit (compound 1a) was identified through screening the Pharmacopeia ECLiPS compound collection. SAR modification led to the identification of a short acting triaminotriazine aniline methoxyamide (compound 1m) possessing in vitro and in vivo oral activity in animal models of acute and chronic inflammatory disease. An X-ray crystal structure of compound 1m in this class, cocrystallized with unactivated p38a protein, indicates that these compounds bind to the ATP binding pocket and possess key H-bonding interactions within a deeper cleft. Hydrogen bonding between one of the triazine nitrogens and the backbone NH of the Met109 residue occurs through a water molecule. The methoxyamide NH and carbonyl oxygen are within H-bonding distance of Glu71 and Asp168.",

author = "Katerina Leftheris and Gulzar Ahmed and Ran Chan and Dyckman, {Alaric J.} and Zahid Hussain and Kan Ho and John Hynes and Jeffrey Letourneau and Wei Li and Shuqun Lin and Axel Metzger and Moriarty, {Kevin J.} and Chris Riviello and Yvonne Shimshock and James Wen and John Wityak and Wrobleski, {Stephen T.} and Hong Wu and Junjun Wu and Madhuri Desai and Gillooly, {Kathleen M.} and Lin, {Tsung H.} and Derek Loo and McIntyre, {Kim W.} and Sidney Pitt and Shen, {Ding Ren} and Shuster, {David J.} and Rosemary Zhang and David Diller and Arthur Doweyko and John Sack and Jack Baldwin and Joel Barrish and John Dodd and Ian Henderson and Steve Kanner and Schieven, {Gary L.} and Maria Webb",

year = "2004",

month = dec,

day = "2",

doi = "10.1021/jm049521d",

language = "English (US)",

volume = "47",

pages = "6283--6291",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "25",

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Leftheris, K, Ahmed, G, Chan, R, Dyckman, AJ, Hussain, Z, Ho, K, Hynes, J, Letourneau, J, Li, W, Lin, S, Metzger, A, Moriarty, KJ, Riviello, C, Shimshock, Y, Wen, J, Wityak, J, Wrobleski, ST, Wu, H, Wu, J, Desai, M, Gillooly, KM, Lin, TH, Loo, D, McIntyre, KW, Pitt, S, Shen, DR, Shuster, DJ, Zhang, R, Diller, D, Doweyko, A, Sack, J, Baldwin, J, Barrish, J, Dodd, J, Henderson, I, Kanner, S, Schieven, GL & Webb, M 2004, 'The discovery of orally active triaminotriazine aniline amides as inhibitors of p38 MAP kinase', Journal of Medicinal Chemistry, vol. 47, no. 25, pp. 6283-6291. https://doi.org/10.1021/jm049521d

TY - JOUR

T1 - The discovery of orally active triaminotriazine aniline amides as inhibitors of p38 MAP kinase

AU - Leftheris, Katerina

AU - Ahmed, Gulzar

AU - Chan, Ran

AU - Dyckman, Alaric J.

AU - Hussain, Zahid

AU - Ho, Kan

AU - Hynes, John

AU - Letourneau, Jeffrey

AU - Li, Wei

AU - Lin, Shuqun

AU - Metzger, Axel

AU - Moriarty, Kevin J.

AU - Riviello, Chris

AU - Shimshock, Yvonne

AU - Wen, James

AU - Wityak, John

AU - Wrobleski, Stephen T.

AU - Wu, Hong

AU - Wu, Junjun

AU - Desai, Madhuri

AU - Gillooly, Kathleen M.

AU - Lin, Tsung H.

AU - Loo, Derek

AU - McIntyre, Kim W.

AU - Pitt, Sidney

AU - Shen, Ding Ren

AU - Shuster, David J.

AU - Zhang, Rosemary

AU - Diller, David

AU - Doweyko, Arthur

AU - Sack, John

AU - Baldwin, Jack

AU - Barrish, Joel

AU - Dodd, John

AU - Henderson, Ian

AU - Kanner, Steve

AU - Schieven, Gary L.

AU - Webb, Maria

PY - 2004/12/2

Y1 - 2004/12/2

N2 - A new structural class of triaminotriazine aniline amides possessing potent p38 enzyme activity has been discovered. The initial hit (compound 1a) was identified through screening the Pharmacopeia ECLiPS compound collection. SAR modification led to the identification of a short acting triaminotriazine aniline methoxyamide (compound 1m) possessing in vitro and in vivo oral activity in animal models of acute and chronic inflammatory disease. An X-ray crystal structure of compound 1m in this class, cocrystallized with unactivated p38a protein, indicates that these compounds bind to the ATP binding pocket and possess key H-bonding interactions within a deeper cleft. Hydrogen bonding between one of the triazine nitrogens and the backbone NH of the Met109 residue occurs through a water molecule. The methoxyamide NH and carbonyl oxygen are within H-bonding distance of Glu71 and Asp168.

AB - A new structural class of triaminotriazine aniline amides possessing potent p38 enzyme activity has been discovered. The initial hit (compound 1a) was identified through screening the Pharmacopeia ECLiPS compound collection. SAR modification led to the identification of a short acting triaminotriazine aniline methoxyamide (compound 1m) possessing in vitro and in vivo oral activity in animal models of acute and chronic inflammatory disease. An X-ray crystal structure of compound 1m in this class, cocrystallized with unactivated p38a protein, indicates that these compounds bind to the ATP binding pocket and possess key H-bonding interactions within a deeper cleft. Hydrogen bonding between one of the triazine nitrogens and the backbone NH of the Met109 residue occurs through a water molecule. The methoxyamide NH and carbonyl oxygen are within H-bonding distance of Glu71 and Asp168.

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U2 - 10.1021/jm049521d

DO - 10.1021/jm049521d

M3 - Article

C2 - 15566298

AN - SCOPUS:9744269944

SN - 0022-2623

VL - 47

SP - 6283

EP - 6291

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 25

ER -

The discovery of orally active triaminotriazine aniline amides as inhibitors of p38 MAP kinase

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