5 research outputs found
Chemoselective One-Pot Synthesis of Functionalized Amino-azaheterocycles Enabled by COware
Functionalized
bicyclic amino-azaheterocycles are rapidly accessed
in a one-pot cross-coupling/reduction sequence enabled by the use
of COware. Incompatible reagents are physically separated in a single
reaction vessel to effect two chemoselective transformationsSuzuki–Miyaura
cross-coupling and heteroarene reduction. The developed method allows
access to novel heterocyclic templates, including semisaturated Hedgehog
and dual PI3K/mTOR inhibitors, which show enhanced physicochemical
properties compared to their unsaturated counterparts
Investigation of a Bicyclo[1.1.1]pentane as a Phenyl Replacement within an LpPLA<sub>2</sub> Inhibitor
We describe the incorporation
of a bicyclo[1.1.1]pentane moiety
within two known LpPLA<sub>2</sub> inhibitors to act as bioisosteric
phenyl replacements. An efficient synthesis to the target compounds
was enabled with a dichlorocarbene insertion into a bicyclo[1.1.0]butane
system being the key transformation. Potency, physicochemical, and
X-ray crystallographic data were obtained to compare the known inhibitors
to their bioisosteric counterparts, which showed the isostere was
well tolerated and positively impacted on the physicochemical profile
Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA<sub>2</sub>)
Lp-PLA<sub>2</sub> has been explored as a target for a number of
inflammation associated diseases, including cardiovascular disease
and dementia. This article describes the discovery of a new fragment
derived chemotype that interacts with the active site of Lp-PLA<sub>2</sub>. The starting fragment hit was discovered through an X-ray
fragment screen and showed no activity in the bioassay (IC<sub>50</sub> > 1 mM). The fragment hit was optimized using a variety of structure-based
drug design techniques, including virtual screening, fragment merging,
and improvement of shape complementarity. A novel series of Lp-PLA<sub>2</sub> inhibitors was generated with low lipophilicity and a promising
pharmacokinetic profile
Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA<sub>2</sub>) Discovered through X‑ray Fragment Screening
Elevated levels of
human lipoprotein-associated phospholipase A2
(Lp-PLA<sub>2</sub>) are associated with cardiovascular disease and
dementia. A fragment screen was conducted against Lp-PLA<sub>2</sub> in order to identify novel inhibitors. Multiple fragment hits were
observed in different regions of the active site, including some hits
that bound in a pocket created by movement of a protein side chain
(approximately 13 Å from the catalytic residue Ser273). Using
structure guided design, we optimized a fragment that bound in this
pocket to generate a novel low nanomolar chemotype, which did not
interact with the catalytic residues
Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA<sub>2</sub>) Discovered through X‑ray Fragment Screening
Elevated levels of
human lipoprotein-associated phospholipase A2
(Lp-PLA<sub>2</sub>) are associated with cardiovascular disease and
dementia. A fragment screen was conducted against Lp-PLA<sub>2</sub> in order to identify novel inhibitors. Multiple fragment hits were
observed in different regions of the active site, including some hits
that bound in a pocket created by movement of a protein side chain
(approximately 13 Å from the catalytic residue Ser273). Using
structure guided design, we optimized a fragment that bound in this
pocket to generate a novel low nanomolar chemotype, which did not
interact with the catalytic residues