5 research outputs found
Novel Acidic 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitor with Reduced Acyl Glucuronide Liability: The Discovery of 4‑[4-(2-Adamantylcarbamoyl)-5-<i>tert</i>-butyl-pyrazol-1-yl]benzoic Acid (AZD8329)
Inhibition of 11β-HSD1 is viewed as a potential
target for
the treatment of obesity and other elements of the metabolic syndrome.
We report here the optimization of a carboxylic acid class of inhibitors
from AZD4017 (<b>1</b>) to the development candidate AZD8329
(<b>27</b>). A structural change from pyridine to pyrazole together
with structural optimization led to an improved technical profile
in terms of both solubility and pharmacokinetics. The extent of acyl
glucuronidation was reduced through structural optimization of both
the carboxylic acid and amide substituents, coupled with a reduction
in lipophilicity leading to an overall increase in metabolic stability
Discovery of a Potent, Selective, and Orally Bioavailable Acidic 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitor: Discovery of 2-[(3<i>S</i>)-1-[5-(Cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]-3-piperidyl]acetic Acid (AZD4017)
Inhibition of 11β-HSD1 is an attractive mechanism
for the
treatment of obesity and other elements of the metabolic syndrome.
We report here the discovery of a nicotinic amide derived carboxylic
acid class of inhibitors that has good potency, selectivity, and pharmacokinetic
characteristics. Compound <b>11i</b> (AZD4017) is an effective
inhibitor of 11β-HSD1 in human adipocytes and exhibits good
druglike properties and as a consequence was selected for clinical
development
Discovery of Pyrazolo[1,5‑<i>a</i>]pyrimidine B‑Cell Lymphoma 6 (BCL6) Binders and Optimization to High Affinity Macrocyclic Inhibitors
Inhibition of the protein–protein
interaction between B-cell
lymphoma 6 (BCL6) and corepressors has been implicated as a therapeutic
target in diffuse large B-cell lymphoma (DLBCL) cancers and profiling
of potent and selective BCL6 inhibitors are critical to test this
hypothesis. We identified a pyrazoloÂ[1,5-<i>a</i>]Âpyrimidine
series of BCL6 binders from a fragment screen in parallel with a virtual
screen. Using structure-based drug design, binding affinity was increased
100000-fold. This involved displacing crystallographic water, forming
new ligand–protein interactions and a macrocyclization to favor
the bioactive conformation of the ligands. Optimization for slow off-rate
constant kinetics was conducted as well as improving selectivity against
an off-target kinase, CK2. Potency in a cellular BCL6 assay was further
optimized to afford highly selective probe molecules. Only weak antiproliferative
effects were observed across a number of DLBCL lines and a multiple
myeloma cell line without a clear relationship to BCL6 potency. As
a result, we conclude that the BCL6 hypothesis in DLBCL cancer remains
unproven
Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl‑1 Inhibitors
Mcl-1 is a pro-apoptotic
BH3 protein family member similar to Bcl-2
and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors
and allows cancer cells to evade apoptosis. Here we report the discovery
and optimization of a series of non-natural peptide Mcl-1 inhibitors.
Screening of DNA-encoded libraries resulted in hit compound <b>1</b>, a 1.5 ÎĽM Mcl-1 inhibitor. A subsequent crystal structure
demonstrated that compound <b>1</b> bound to Mcl-1 in a β-turn
conformation, such that the two ends of the peptide were close together.
This proximity allowed for the linking of the two ends of the peptide
to form a macrocycle. Macrocyclization resulted in an approximately
10-fold improvement in binding potency. Further exploration of a key
hydrophobic interaction with Mcl-1 protein and also with the moiety
that engages Arg256 led to additional potency improvements. The use
of protein–ligand crystal structures and binding kinetics contributed
to the design and understanding of the potency gains. Optimized compound <b>26</b> is a <3 nM Mcl-1 inhibitor, while inhibiting Bcl-2 at
only 5 ÎĽM and Bcl-xL at >99 ÎĽM, and induces cleaved
caspase-3
in MV4–11 cells with an IC<sub>50</sub> of 3 μM after
6 h
Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl‑1 Inhibitors
Mcl-1 is a pro-apoptotic
BH3 protein family member similar to Bcl-2
and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors
and allows cancer cells to evade apoptosis. Here we report the discovery
and optimization of a series of non-natural peptide Mcl-1 inhibitors.
Screening of DNA-encoded libraries resulted in hit compound <b>1</b>, a 1.5 ÎĽM Mcl-1 inhibitor. A subsequent crystal structure
demonstrated that compound <b>1</b> bound to Mcl-1 in a β-turn
conformation, such that the two ends of the peptide were close together.
This proximity allowed for the linking of the two ends of the peptide
to form a macrocycle. Macrocyclization resulted in an approximately
10-fold improvement in binding potency. Further exploration of a key
hydrophobic interaction with Mcl-1 protein and also with the moiety
that engages Arg256 led to additional potency improvements. The use
of protein–ligand crystal structures and binding kinetics contributed
to the design and understanding of the potency gains. Optimized compound <b>26</b> is a <3 nM Mcl-1 inhibitor, while inhibiting Bcl-2 at
only 5 ÎĽM and Bcl-xL at >99 ÎĽM, and induces cleaved
caspase-3
in MV4–11 cells with an IC<sub>50</sub> of 3 μM after
6 h