p38alpha mitogen-activated protein kinase inhibitors: optimization of a series of biphenylamides to give a molecule suitable for clinical progression.

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Aston NM, Bamborough P, Buckton JB, Edwards CD, Holmes DS, Jones KL, Patel VK, Smee PA, Somers DO, Vitulli G, Walker AL

p38alpha mitogen-activated protein kinase inhibitors: optimization of a series of biphenylamides to give a molecule suitable for clinical progression.

J Med Chem. 2009 Oct 22;52(20):6257-69. doi: 10.1021/jm9004779.

PubMed ID

19772287 [ View in PubMed

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Abstract

p38alpha MAP kinase is a key anti-inflammatory target for rheumatoid arthritis, influencing biosynthesis of pro-inflammatory cytokines TNFalpha and IL-1beta at a translational and transcriptional level. In this paper, we describe how we have optimized a series of novel p38alpha/beta inhibitors using crystal structures of our inhibitors bound to p38alpha, classical medicinal chemistry, and modeling of virtual libraries to derive a molecule suitable for progression into clinical development.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
N~3~-cyclopropyl-N~4~'-(cyclopropylmethyl)-6-methylbiphenyl-3,4'-dicarboxamide	Mitogen-activated protein kinase 14	Ki (nM)	12.59	N/A	N/A	Details
N~3~-cyclopropyl-N~4~'-(cyclopropylmethyl)-6-methylbiphenyl-3,4'-dicarboxamide	Mitogen-activated protein kinase 14	IC 50 (nM)	200	N/A	N/A	Details
N~3~-cyclopropyl-N~4~'-(cyclopropylmethyl)-6-methylbiphenyl-3,4'-dicarboxamide	Mitogen-activated protein kinase 14	IC 50 (nM)	1584.89	N/A	N/A	Details