Hydrazinonaphthalene and azonaphthalene thrombopoietin mimics are nonpeptidyl promoters of megakaryocytopoiesis

J Med Chem. 2001 Oct 25;44(22):3730-45. doi: 10.1021/jm010283l.

K J Duffy ¹, M G Darcy, E Delorme, S B Dillon, D F Eppley, C Erickson-Miller, L Giampa, C B Hopson, Y Huang, R M Keenan, P Lamb, L Leong, N Liu, S G Miller, A T Price, J Rosen, R Shah, T N Shaw, H Smith, K C Stark, S S Tian, C Tyree, K J Wiggall, L Zhang, J I Luengo

Affiliations

Affiliation

1 GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA. [email protected]

PMID: 11606138 DOI: 10.1021/jm010283l

Abstract

High-throughput screening for the induction of a luciferase reporter gene in a thrombopoietin (TPO)-responsive cell line resulted in the identification of 4-diazo-3-hydroxy-1-naphthalenesulfonic acids as TPO mimics. Modification of the core structure and adjustment of unwanted functionality resulted in the development of (5-oxo-1,5-dihydropyrazol-4-ylidene)hydrazines which exhibited efficacies equivalent to those of TPO in several cell-based assays designed to measure thrombopoietic activity. Furthermore, these compounds elicited biochemical responses in TPO-receptor-expressing cells similar to those in TPO itself, including kinase activation and protein phosphorylation. Potencies for the best compounds were high for such low molecular weight compounds (MW < 500) with EC(50) values in the region of 1-20 nM.

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