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 transformationsīøSuzukiāMiyaura
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]Āpentane 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]Ābutane
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
Identification and Optimization of a Ligand-Efficient Benzoazepinone Bromodomain and Extra Terminal (BET) Family Acetyl-Lysine Mimetic into the Oral Candidate Quality Molecule IāBET432
The
bromodomain and extra terminal (BET) family of proteins
are
an integral part of human epigenome regulation, the dysregulation
of which is implicated in multiple oncology and inflammatory diseases.
Disrupting the BET family bromodomain acetyl-lysine (KAc) histone
proteināprotein interaction with small-molecule KAc mimetics
has proven to be a disease-relevant mechanism of action, and multiple
molecules are currently undergoing oncology clinical trials. This
work describes an efficiency analysis of published GSK pan-BET bromodomain
inhibitors, which drove a strategic choice to focus on the identification
of a ligand-efficient KAc mimetic with the hypothesis that lipophilic
efficiency could be drastically improved during optimization. This
focus drove the discovery of the highly ligand-efficient and structurally
distinct benzoazepinone KAc mimetic. Following crystallography to
identify suitable growth vectors, the benzoazepinone core was optimized
through an explore-exploit structureāactivity relationship
(SAR) approach while carefully monitoring lipophilic efficiency to
deliver I-BET432 (41) as an oral candidate quality molecule
Identification and Optimization of a Ligand-Efficient Benzoazepinone Bromodomain and Extra Terminal (BET) Family Acetyl-Lysine Mimetic into the Oral Candidate Quality Molecule IāBET432
The
bromodomain and extra terminal (BET) family of proteins
are
an integral part of human epigenome regulation, the dysregulation
of which is implicated in multiple oncology and inflammatory diseases.
Disrupting the BET family bromodomain acetyl-lysine (KAc) histone
proteināprotein interaction with small-molecule KAc mimetics
has proven to be a disease-relevant mechanism of action, and multiple
molecules are currently undergoing oncology clinical trials. This
work describes an efficiency analysis of published GSK pan-BET bromodomain
inhibitors, which drove a strategic choice to focus on the identification
of a ligand-efficient KAc mimetic with the hypothesis that lipophilic
efficiency could be drastically improved during optimization. This
focus drove the discovery of the highly ligand-efficient and structurally
distinct benzoazepinone KAc mimetic. Following crystallography to
identify suitable growth vectors, the benzoazepinone core was optimized
through an explore-exploit structureāactivity relationship
(SAR) approach while carefully monitoring lipophilic efficiency to
deliver I-BET432 (41) as an oral candidate quality molecule