4 research outputs found
An Orally Available BACE1 Inhibitor That Affords Robust CNS Aβ Reduction without Cardiovascular Liabilities
BACE1
inhibition to prevent Aβ peptide formation is considered
to be a potential route to a disease-modifying treatment for Alzheimer’s
disease. Previous efforts in our laboratory using a combined structure-
and property-based approach have resulted in the identification of
aminooxazoline xanthenes as potent BACE1 inhibitors. Herein, we report
further optimization leading to the discovery of inhibitor <b>15</b> as an orally available and highly efficacious BACE1 inhibitor that
robustly reduces CSF and brain Aβ levels in both rats and nonhuman
primates. In addition, compound <b>15</b> exhibited low activity
on the hERG ion channel and was well tolerated in an integrated cardiovascular
safety model
Discovery of CMX990: A Potent SARS-CoV‑2 3CL Protease Inhibitor Bearing a Novel Warhead
There remains a need to develop novel SARS-CoV-2 therapeutic
options
that improve upon existing therapies by an increased robustness of
response, fewer safety liabilities, and global-ready accessibility.
Functionally critical viral main protease (Mpro, 3CLpro) of SARS-CoV-2 is an attractive target due to its homology
within the coronaviral family, and lack thereof toward human proteases.
In this disclosure, we outline the advent of a novel SARS-CoV-2 3CLpro inhibitor, CMX990, bearing an unprecedented
trifluoromethoxymethyl ketone warhead. Compared with the marketed
drug nirmatrelvir (combination with ritonavir = Paxlovid), CMX990 has distinctly differentiated potency (∼5× more potent
in primary cells) and human in vitro clearance (>4×
better microsomal clearance and >10× better hepatocyte clearance),
with good in vitro-to-in vivo correlation.
Based on its compelling preclinical profile and projected once or
twice a day dosing supporting unboosted oral therapy in humans, CMX990 advanced to a Phase 1 clinical trial as an oral drug
candidate for SARS-CoV-2
Discovery of CMX990: A Potent SARS-CoV‑2 3CL Protease Inhibitor Bearing a Novel Warhead
There remains a need to develop novel SARS-CoV-2 therapeutic
options
that improve upon existing therapies by an increased robustness of
response, fewer safety liabilities, and global-ready accessibility.
Functionally critical viral main protease (Mpro, 3CLpro) of SARS-CoV-2 is an attractive target due to its homology
within the coronaviral family, and lack thereof toward human proteases.
In this disclosure, we outline the advent of a novel SARS-CoV-2 3CLpro inhibitor, CMX990, bearing an unprecedented
trifluoromethoxymethyl ketone warhead. Compared with the marketed
drug nirmatrelvir (combination with ritonavir = Paxlovid), CMX990 has distinctly differentiated potency (∼5× more potent
in primary cells) and human in vitro clearance (>4×
better microsomal clearance and >10× better hepatocyte clearance),
with good in vitro-to-in vivo correlation.
Based on its compelling preclinical profile and projected once or
twice a day dosing supporting unboosted oral therapy in humans, CMX990 advanced to a Phase 1 clinical trial as an oral drug
candidate for SARS-CoV-2
Oxopyrido[2,3‑<i>d</i>]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors
In nonsmall cell lung cancer (NSCLC),
the threonine<sup>790</sup>–methionine<sup>790</sup> (T790M)
point mutation of EGFR kinase
is one of the leading causes of acquired resistance to the first generation
tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib.
Herein, we describe the optimization of a series of 7-oxopyridoÂ[2,3-<i>d</i>]Âpyrimidinyl-derived irreversible inhibitors of EGFR kinase.
This led to the discovery of compound <b>24</b> which potently
inhibits gefitinib-resistant EGFR<sup>L858R,T790M</sup> with 100-fold
selectivity over wild-type EGFR. Compound <b>24</b> displays
strong antiproliferative activity against the H1975 nonsmall cell
lung cancer cell line, the first line mutant HCC827 cell line, and
promising antitumor activity in an EGFR<sup>L858R,T790M</sup> driven
H1975 xenograft model sparing the side effects associated with the
inhibition of wild-type EGFR