4 research outputs found
Synthesis of 3‑(Hetero)aryl Tetrahydropyrazolo[3,4‑<i>c</i>]pyridines by Suzuki–Miyaura Cross-Coupling Methodology
A new
synthetic route to 3-(heteroaryl) tetrahydropyrazoloÂ[3,4-<i>c</i>]Âpyridines has been developed that uses the Suzuki–Miyaura
cross-coupling of a triflate <b>6</b> with (hetero)Âaryl
boronic acids or esters. Using PdÂ(OAc)<sub>2</sub> and XPhos or an
XPhos precatalyst, a diverse range of substituents at the C3 position
of the tetrahydropyrazoloÂ[3,4-<i>c</i>]Âpyridine
skeleton were prepared. The use of pivaloyloxymethyl and benzyl protection
also offers the potential to differentially functionalize the pyrazole
and tetrahydropyridine nitrogens
Optimization of Brain Penetrant 11β-Hydroxysteroid Dehydrogenase Type I Inhibitors and in Vivo Testing in Diet-Induced Obese Mice
11β-Hydroxysteroid
dehydrogenase type 1 (11β-HSD1)
has been widely considered by the pharmaceutical industry as a target
to treat metabolic syndrome in type II diabetics. We hypothesized
that central nervous system (CNS) penetration might be required to
see efficacy. Starting from a previously reported pyrimidine compound,
we removed hydrogen-bond donors to yield <b>3</b>, which had
modest CNS penetration. More significant progress was achieved by
changing the core to give <b>40</b>, which combines good potency
and CNS penetration. Compound <b>40</b> was dosed to diet-induced
obese (DIO) mice and gave excellent target engagement in the liver
and high free exposures of drug, both peripherally and in the CNS.
However, no body weight reduction or effects on glucose or insulin
were observed in this model. Similar data were obtained with a structurally
diverse thiazole compound <b>51</b>. This work casts doubt on
the hypothesis that localized tissue modulation of 11β-HSD1
activity alleviates metabolic syndrome
Design and Optimization of Pyrazinecarboxamide-Based Inhibitors of Diacylglycerol Acyltransferase 1 (DGAT1) Leading to a Clinical Candidate Dimethylpyrazinecarboxamide Phenylcyclohexylacetic Acid (AZD7687)
A new series of pyrazinecarboxamide DGAT1 inhibitors
was designed to address the need for a candidate drug with good potency,
selectivity, and physical and DMPK properties combined with a low
predicted dose in man. Rational design and optimization of this series
led to the discovery of compound <b>30</b> (AZD7687), which
met the project objectives for potency, selectivity, in particular
over ACAT1, solubility, and preclinical PK profiles. This compound
showed the anticipated excellent pharmacokinetic properties in human
volunteers
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