We
report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine
derivatives and their subsequent optimization, guided by structure-based
design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent
JmjC histone N-methyl lysine demethylase (KDM) inhibitors
which bind to Fe(II) in the active site. Substitution from C4 of the
pyrazole moiety allows access to the histone peptide substrate binding
site; incorporation of a conformationally constrained 4-phenylpiperidine
linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and
KDM5 (JARID1) subfamily demethylases, selectivity over representative
exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability
in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay.
The ChEMBL database was mined to efficiently assemble an ion channel-focused screening library. The compiled library consists of 3241 compounds representing 123 templates across nine ion channel categories. Compounds in the screening library are annotated with their respective ion channel category to facilitate back-tracing of prospective molecular targets from phenotypic screening results. The established workflow is adaptable to the construction of focused screening libraries for other therapeutic target classes with diverse recognition motifs.
Crystallography has guided the hybridization
of two series of Trypanosoma bruceiN-myristoyltransferase
(NMT) inhibitors, leading to a novel highly selective series. The
effect of combining the selectivity enhancing elements from two pharmacophores
is shown to be additive and has led to compounds that have greater
than 1000-fold selectivity for TbNMT vs HsNMT. Further optimization of the hybrid series has identified compounds
with significant trypanocidal activity capable of crossing the blood–brain
barrier. By using CF-1 mdr1a deficient mice, we were able to demonstrate
full cures in vivo in a mouse model of stage 2 African sleeping sickness.
This and previous work provides very strong validation for NMT as
a drug target for human African trypanosomiasis in both the peripheral
and central nervous system stages of disease.
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