13 research outputs found
Enantioselective Organocatalytic Cyclopropanations. The Identification of a New Class of Iminium Catalyst Based upon Directed Electrostatic Activation
A new method for enantioselective organocatalytic cyclopropanation is described. This study outlines the identification of a new class of iminium catalyst based on the concept of directed electrostatic activation (DEA). This novel organocatalytic mechanism exploits dual activation of ylide and enal substrates through a proposed electrostatic activation and stereodirected protocol. Formation of trisubstituted cyclopropanes with high levels of enantio- and diastereoinduction is accomplished for a variety of α,β-unsaturated aldehydes and sulfonium ylides. In addition, mechanistic studies have found that this cyclopropanation reaction exhibits enantioselectivity and reactivity profiles that are in accord with the proposed DEA step
Enantioselective Organocatalytic Cyclopropanations. The Identification of a New Class of Iminium Catalyst Based upon Directed Electrostatic Activation
Discovery of Phosphodiesterase 10A (PDE10A) PET Tracer AMG 580 to Support Clinical Studies
We
report the discovery of PDE10A PET tracer AMG 580 developed
to support proof of concept studies with PDE10A inhibitors in the
clinic. To find a tracer with higher binding potential (BP<sub>ND</sub>) in NHP than our previously reported tracer <b>1</b>, we implemented
a surface plasmon resonance assay to measure the binding off-rate
to identify candidates with slower washout rate in vivo. Five candidates
(<b>2</b>–<b>6</b>) from two structurally distinct
scaffolds were identified that possessed both the in vitro characteristics
that would favor central penetration and the structural features necessary
for PET isotope radiolabeling. Two cinnolines (<b>2</b>, <b>3</b>) and one keto-benzimidazole (<b>5</b>) exhibited PDE10A
target specificity and brain uptake comparable to or better than <b>1</b> in the in vivo LC–MS/MS kinetics distribution study
in SD rats. In NHP PET imaging study, [<sup>18</sup>F]-<b>5</b> produced a significantly improved BP<sub>ND</sub> of 3.1 and was
nominated as PDE10A PET tracer clinical candidate for further studies
Discovery of Aryl Aminoquinazoline Pyridones as Potent, Selective, and Orally Efficacious Inhibitors of Receptor Tyrosine Kinase c-Kit â€
AMG 580: A Novel Small Molecule Phosphodiesterase 10A (PDE10A) Positron Emission Tomography Tracer
Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 3. Structure–Activity Relationships within the Aryl Carbinol Region of the <i>N</i>‑Arylsulfonamido‑<i>N</i>′‑arylpiperazine Series
We have recently reported a novel
approach to increase cytosolic
glucokinase (GK) levels through the binding of a small molecule to
its endogenous inhibitor, glucokinase regulatory protein (GKRP). These
initial investigations culminated in the identification of 2-(4-((2<i>S</i>)-4-((6-amino-3-pyridinyl)Âsulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)Âphenyl)-1,1,1,3,3,3-hexafluoro-2-propanol
(<b>1</b>, AMG-3969), a compound that effectively enhanced GK
translocation and reduced blood glucose levels in diabetic animals.
Herein we report the results of our expanded SAR investigations that
focused on modifications to the aryl carbinol group of this series.
Guided by the X-ray cocrystal structure of compound <b>1</b> bound to hGKRP, we identified several potent GK–GKRP disruptors
bearing a diverse set of functionalities in the aryl carbinol region.
Among them, sulfoximine and pyridinyl derivatives <b>24</b> and <b>29</b> possessed excellent potency as well as favorable PK properties.
When dosed orally in <i>db</i>/<i>db</i> mice,
both compounds significantly lowered fed blood glucose levels (up
to 58%)
Discovery of Clinical Candidate 1‑(4-(3-(4-(1<i>H</i>‑Benzo[<i>d</i>]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone (AMG 579), A Potent, Selective, and Efficacious Inhibitor of Phosphodiesterase 10A (PDE10A)
We report the identification of a
PDE10A clinical candidate by
optimizing potency and in vivo efficacy of promising keto-benzimidazole
leads <b>1</b> and <b>2</b>. Significant increase in biochemical
potency was observed when the saturated rings on morpholine <b>1</b> and <i>N</i>-acetyl piperazine <b>2</b> were
changed by a single atom to tetrahydropyran <b>3</b> and <i>N</i>-acetyl piperidine <b>5</b>. A second single atom
modification from pyrazines <b>3</b> and <b>5</b> to pyridines <b>4</b> and <b>6</b> improved the inhibitory activity of <b>4</b> but not <b>6</b>. In the in vivo LC–MS/MS target
occupancy (TO) study at 10 mg/kg, <b>3</b>, <b>5</b>,
and <b>6</b> achieved 86–91% occupancy of PDE10A in the
brain. Furthermore, both CNS TO and efficacy in PCP-LMA behavioral
model were observed in a dose dependent manner. With superior in vivo
TO, in vivo efficacy and in vivo PK profiles in multiple preclinical
species, compound <b>5</b> (AMG 579) was advanced as our PDE10A
clinical candidate