2 research outputs found
Synthesis of 4‑Arylthieno[2,3‑<i>b</i>]pyridines and 4‑Aminothieno[2,3‑<i>b</i>]pyridines via a Regioselective Bromination of Thieno[2,3‑<i>b</i>]pyridine
The first regioselective, mild bromination
of thienoÂ[2,3-<i>b</i>]Âpyridine is described herein. The
reaction proceeds with
selectivity toward the 4-position (87% isolated yield). Subsequent
cross-coupling reactions proceed in excellent yields and demonstrate
the potential of 4-bromothienoÂ[2,3-<i>b</i>]Âpyridine as
a building block for use in drug discovery research
Pyrimidinone Nicotinamide Mimetics as Selective Tankyrase and Wnt Pathway Inhibitors Suitable for in Vivo Pharmacology
The canonical Wnt pathway plays an
important role in embryonic
development, adult tissue homeostasis, and cancer. Germline mutations
of several Wnt pathway components, such as Axin, APC, and ß-catenin,
can lead to oncogenesis. Inhibition of the polyÂ(ADP-ribose) polymerase
(PARP) catalytic domain of the tankyrases (TNKS1 and TNKS2) is known
to inhibit the Wnt pathway via increased stabilization of Axin. In
order to explore the consequences of tankyrase and Wnt pathway inhibition
in preclinical models of cancer and its impact on normal tissue, we
sought a small molecule inhibitor of TNKS1/2 with suitable physicochemical
properties and pharmacokinetics for hypothesis testing in vivo. Starting
from a 2-phenyl quinazolinone hit (compound <b>1</b>), we discovered
the pyrrolopyrimidinone compound <b>25</b> (AZ6102), which is
a potent TNKS1/2 inhibitor that has 100-fold selectivity against other
PARP family enzymes and shows 5 nM Wnt pathway inhibition in DLD-1
cells. Moreover, compound <b>25</b> can be formulated well in
a clinically relevant intravenous solution at 20 mg/mL, has demonstrated
good pharmacokinetics in preclinical species, and shows low Caco2
efflux to avoid possible tumor resistance mechanisms