7 research outputs found
De Novo Fragment Design: A Medicinal Chemistry Approach to Fragment-Based Lead Generation
The use of fragments with low binding
affinity for their targets
as starting points has received much attention recently. Screening
of fragment libraries has been the most common method to find attractive
starting points. Herein, we describe a unique, alternative approach
to generating fragment leads. A binding model was developed and a
set of guidelines were then selected to use this model to design fragments,
enabling our discovery of a novel fragment with high LE
Cell Active Hydroxylactam Inhibitors of Human Lactate Dehydrogenase with Oral Bioavailability in Mice
A series
of trisubstituted hydroxylactams was identified as potent
enzymatic and cellular inhibitors of human lactate dehydrogenase A.
Utilizing structure-based design and physical property optimization,
multiple inhibitors were discovered with <10 μM lactate IC<sub>50</sub> in a MiaPaca2 cell line. Optimization of the series led
to <b>29</b>, a potent cell active molecule (MiaPaca2 IC<sub>50</sub> = 0.67 μM) that also possessed good exposure when
dosed orally to mice
Identification of <i>C</i>‑2 Hydroxyethyl Imidazopyrrolopyridines as Potent JAK1 Inhibitors with Favorable Physicochemical Properties and High Selectivity over JAK2
Herein we report on the structure-based
discovery of a <i>C</i>-2 hydroxyethyl moiety which provided
consistently high
levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine
series of JAK1 inhibitors. X-ray structures of a <i>C</i>-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed
differential ligand/protein interactions between the two isoforms
and offered an explanation for the observed selectivity. Analysis
of historical data from related molecules was used to develop a set
of physicochemical compound design parameters to impart desirable
properties such as acceptable membrane permeability, potent whole
blood activity, and a high degree of metabolic stability. This work
culminated in the identification of a highly JAK1 selective compound
(<b>31</b>) exhibiting favorable oral bioavailability across
a range of preclinical species and robust efficacy in a rat CIA model