7 research outputs found
Convergent Syntheses of Isomeric Imidazolospiroketones as Templates for Acetyl-CoA Carboxylase (ACC) Inhibitors
The synthesis of imidazole fused spirocyclic ketones
as templates
for acetyl-CoA carboxylase (ACC) inhibitors is reported. By completing
the spirocyclic ring closure via divergent pathways, the synthesis
of these regioisomers from common intermediates was developed. Through
an aldehyde homologation/transmetalation strategy, one isomer was
formed selectively. The second desired isomer was obtained via an
intramolecular aromatic homolytic substitution reaction. Preparation
of these isomeric spiroketones provided templates which, upon elaboration,
led to key structure–activity relationship (SAR) points for
delivery of potent ACC inhibitors
The Synthesis of Methyl-Substituted Spirocyclic Piperidine-Azetidine (2,7-Diazaspiro[3.5]nonane) and Spirocyclic Piperidine-Pyrrolidine (2,8-Diazaspiro[4.5]decane) Ring Systems
The synthesis of
a series of pharmaceutically important <i>N</i>-protected
methyl-substituted spirocyclic piperidine-azetidine
(2,7-diazaspiro[3.5]nonane) and spirocyclic piperidine-pyrrolidine
(2,8-diazaspiro[4.5]decane) ring systems was developed.
These motifs contain two differentiated sites (protected secondary
amines) to allow for further functionalization via reductive amination,
amidation, or other chemistry. The methyl-substituted spiroazetidine
ring systems were accessed using nitrile lithiation/alkylation
chemistry while the methyl-substituted spiropyrrolidines were synthesized
by 1,4-addition reactions with nitroalkanes, followed by reduction
and cyclization. These conditions were then scaled for the synthesis
of 1-methyl spirocyclic piperidine-pyrrolidine with a classical resolution
of the product using a tartaric acid derivative to isolate a single
enantiomer
Synthesis of 7-Oxo-dihydrospiro[indazole-5,4′-piperidine] Acetyl-CoA Carboxylase Inhibitors
Synthesis of oxo-dihydrospiroindazole-based acetyl-CoA
carboxylase
(ACC) inhibitors is reported. The dihydrospiroindazoles were assembled
in a regioselective manner in six steps from substituted hydrazines
and protected 4-formylpiperidine. Enhanced regioselectivity in the
condensation between a keto enamine and substituted hydrazines was
observed when using toluene as the solvent, leading to selective formation
of 1-substituted spiroindazoles. The 2-substituted spiroindazoles
were formed selectively from alkyl hydrazones by ring closure with
Vilsmeier reagent. The key step in the elaboration to the final products
is the conversion of an intermediate olefin to the desired ketone
through elimination of HBr from an <i>O-</i>methyl bromohydrin.
This methodology enabled the synthesis of each desired regioisomer
on 50–75 g scale with minimal purification. Acylation of the
resultant spirocyclic amines provided potent ACC inhibitors
Un incontro internazionale sugli effetti dell'innalzamento del livello marino
Cyclic constraints are incorporated
into an 11-residue analogue
of the N-terminus of glucagon-like peptide-1 (GLP-1) to investigate
effects of structure on agonist activity. Cyclization through linking
side chains of residues 2 and 5 or 5 and 9 produced agonists at nM
concentrations in a cAMP assay. 2D NMR and CD spectra revealed an
N-terminal β-turn and a C-terminal helix that differentially
influenced affinity and agonist potency. These structures can inform
development of small molecule agonists of the GLP-1 receptor to treat
type 2 diabetes
Synthesis of Spiropiperidine Lactam Acetyl-CoA Carboxylase Inhibitors
The synthesis of 4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-<i>c</i>]pyridin]-7′(2′<i>H</i>)-one-based
acetyl-CoA carboxylase inhibitors is reported. The hitherto unknown
N-2 <i>tert</i>-butyl pyrazolospirolactam core was synthesized
from ethyl 3-amino-1<i>H</i>-pyrazole-4-carboxylate in a
streamlined 10-step synthesis requiring only one chromatography procedure.
The described synthetic strategy provides pyrazolo-fused spirolactams
from halogenated benzylic arenes and cyclic carboxylates. Key steps
include a regioselective pyrazole alkylation providing the N-2 <i>tert</i>-butyl pyrazole and a Curtius rearrangement under both
conventional and flow conditions to install the hindered amine via
a stable and isolable isocyanate. Finally, a Parham-type cyclization
was used to furnish the desired spirolactam. An analogous route provided
efficient access to the related N-1 isopropyl lactam series. Elaboration
of the lactam cores via amidation enabled synthesis of novel ACC inhibitors
and the identification of potent analogues
Cyclic Penta- and Hexaleucine Peptides without <i>N</i>‑Methylation Are Orally Absorbed
Development of peptide-based drugs
has been severely limited by
lack of oral bioavailability with less than a handful of peptides
being truly orally bioavailable, mainly cyclic peptides with <i>N</i>-methyl amino acids and few hydrogen bond donors. Here
we report that cyclic penta- and hexa-leucine peptides, with no <i>N</i>-methylation and five or six amide NH protons, exhibit
some degree of oral bioavailability (4–17%) approaching that
of the heavily <i>N</i>-methylated drug cyclosporine (22%)
under the same conditions. These simple cyclic peptides demonstrate
that oral bioavailability is achievable for peptides that fall outside
of rule-of-five guidelines without the need for <i>N</i>-methylation or modified amino acids
Decreasing the Rate of Metabolic Ketone Reduction in the Discovery of a Clinical Acetyl-CoA Carboxylase Inhibitor for the Treatment of Diabetes
Acetyl-CoA
carboxylase (ACC) inhibitors offer significant potential
for the treatment of type 2 diabetes mellitus (T2DM), hepatic steatosis,
and cancer. However, the identification of tool compounds suitable
to test the hypothesis in human trials has been challenging. An advanced
series of spirocyclic ketone-containing ACC inhibitors recently reported
by Pfizer were metabolized in vivo by ketone reduction, which complicated
human pharmacology projections. We disclose that this metabolic reduction
can be greatly attenuated through introduction of steric hindrance
adjacent to the ketone carbonyl. Incorporation of weakly basic functionality
improved solubility and led to the identification of <b>9</b> as a clinical candidate for the treatment of T2DM. Phase I clinical
studies demonstrated dose-proportional increases in exposure, single-dose
inhibition of de novo lipogenesis (DNL), and changes in indirect calorimetry
consistent with increased whole-body fatty acid oxidation. This demonstration
of target engagement validates the use of compound <b>9</b> to
evaluate the role of DNL in human disease