7 research outputs found
Tetrahydroisoquinoline Phenols: Selective Estrogen Receptor Downregulator Antagonists with Oral Bioavailability in Rat
A series of tetrahydroisoquinoline
phenols was modified to give
an estrogen receptor downregulator-antagonist profile. Optimization
around the core, alkyl side chain, and pendant aryl ring resulted
in compounds with subnanomolar levels of potency. The phenol functionality
was shown to be required to achieve highly potent compounds, but unusually
this was compatible with obtaining high oral bioavailabilities in
rat
Novel Acidic 11Ī²-Hydroxysteroid Dehydrogenase Type 1 (11Ī²-HSD1) Inhibitor with Reduced Acyl Glucuronide Liability: The Discovery of 4ā[4-(2-Adamantylcarbamoyl)-5-<i>tert</i>-butyl-pyrazol-1-yl]benzoic Acid (AZD8329)
Inhibition of 11Ī²-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 11Ī²-Hydroxysteroid Dehydrogenase Type 1 (11Ī²-HSD1) Inhibitor: Discovery of 2-[(3<i>S</i>)-1-[5-(Cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]-3-piperidyl]acetic Acid (AZD4017)
Inhibition of 11Ī²-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 11Ī²-HSD1 in human adipocytes and exhibits good
druglike properties and as a consequence was selected for clinical
development
Circumventing Seizure Activity in a Series of G Protein Coupled Receptor 119 (GPR119) Agonists
Agonism of GPR119 is viewed as a
potential therapeutic approach
for the treatment of type II diabetes and other elements of metabolic
syndrome. During progression of a previously disclosed candidate <b>1</b> through mice toxicity studies, we observed tonicāclonic
convulsions in several mice at high doses. An in vitro hippocampal
brain slice assay was used to assess the seizure liability of subsequent
compounds, leading to the identification of an aryl sulfone as a replacement
for the 3-cyano pyridyl group. Subsequent optimization to improve
the overall profile, specifically with regard to hERG activity, led
to alkyl sulfone <b>16</b>. This compound did not cause tonicāclonic
convulsions in mice, had a good pharmacokinetic profile, and displayed
in vivo efficacy in murine models. Importantly, it was shown to be
effective in wild-type (WT) but not GPR119 knockout (KO) animals,
consistent with the pharmacology observed being due to agonism of
GPR119
Discovery and Optimization of Pyrrolopyrimidine Inhibitors of Interleukinā1 Receptor Associated Kinase 4 (IRAK4) for the Treatment of Mutant MYD88<sup>L265P</sup> Diffuse Large BāCell Lymphoma
Herein
we report the optimization of a series of pyrrolopyrimidine
inhibitors of interleukin-1 receptor associated kinase 4 (IRAK4) using
X-ray crystal structures and structure based design to identify and
optimize our scaffold. Compound <b>28</b> demonstrated a favorable
physicochemical and kinase selectivity profile and was identified
as a promising in vivo tool with which to explore the role of IRAK4
inhibition in the treatment of mutant MYD88<sup>L265P</sup> diffuse
large B-cell lymphoma (DLBCL). Compound <b>28</b> was shown
to be capable of demonstrating inhibition of NF-ĪŗB activation
and growth of the ABC subtype of DLBCL cell lines in vitro at high
concentrations but showed greater effects in combination with a BTK
inhibitor at lower concentrations. In vivo, the combination of compound <b>28</b> and ibrutinib led to tumor regression in an ABC-DLBCL mouse
model
Potent and Selective Inhibitors of MTH1 Probe Its Role in Cancer Cell Survival
Recent
literature has claimed that inhibition of the enzyme MTH1 can eradicate
cancer. MTH1 is one of the āhousekeepingā enzymes that
are responsible for hydrolyzing damaged nucleotides in cells and thus
prevent them from being incorporated into DNA. We have developed orthogonal
and chemically distinct tool compounds to those published in the literature
to allow us to test the hypothesis that inhibition of MTH1 has wide
applicability in the treatment of cancer. Here we present the work
that led to the discovery of three structurally different series of
MTH1 inhibitors with excellent potency, selectivity, and proven target
engagement in cells. None of these compounds elicited the reported
cellular phenotype, and additional siRNA and CRISPR experiments further
support these observations. Critically, the difference between the
responses of our highly selective inhibitors and published tool compounds
suggests that the effect reported for the latter may be due to off-target
cytotoxic effects. As a result, we conclude that the role of MTH1
in carcinogenesis and utility of its inhibition is yet to be established
Use of Small-Molecule Crystal Structures To Address Solubility in a Novel Series of G Protein Coupled Receptor 119 Agonists: Optimization of a Lead and in Vivo Evaluation
G protein coupled receptor 119 (GPR119) is viewed as
an attractive
target for the treatment of type 2 diabetes and other elements of
the metabolic syndrome. During a program toward discovering agonists
of GPR119, we herein describe optimization of an initial lead compound, <b>2</b>, into a development candidate, <b>42</b>. A key challenge
in this program of work was the insolubility of the lead compound.
Small-molecule crystallography was utilized to understand the intermolecular
interactions in the solid state and resulted in a switch from an aryl
sulphone to a 3-cyanopyridyl motif. The compound was shown to be effective
in wild-type but not knockout animals, confirming that the biological
effects were due to GPR119 agonism