21 research outputs found
Probing Mechanisms of CYP3A Time-Dependent Inhibition Using a Truncated Model System
Time-dependent
inhibition (TDI) of cytochrome P450 (CYP) enzymes may incur serious
undesirable drug–drug interactions and in rare cases drug-induced
idiosyncratic toxicity. The reactive metabolites are often generated
through multiple sequential biotransformations and form adducts with
CYP enzymes to inactivate their function. The complexity of these
processes makes addressing TDI liability very challenging. Strategies
to mitigate TDI are therefore highly valuable in discovering safe
therapies to benefit patients. In this Letter, we disclose our simplified
approach toward addressing CYP3A TDI liabilities, guided by metabolic
mechanism hypotheses. By adding a methyl group onto the α carbon
of a basic amine, TDI activities of both the truncated and full molecules
(<b>7a</b> and <b>11</b>) were completely eliminated.
We propose that truncated molecules, albeit with caveats, may be used
as surrogates for full molecules to investigate TDI
Spirocyclic β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors: From hit to lowering of cerebrospinal fluid (CSF) amyloid β in a higher species
A hallmark of Alzheimer\u27s disease is the brain deposition of amyloid beta (Aβ), a peptide of 36-43 amino acids that is likely a primary driver of neurodegeneration. Aβ is produced by the sequential cleavage of APP by BACE1 and γ-secretase; therefore, inhibition of BACE1 represents an attractive therapeutic target to slow or prevent Alzheimer\u27s disease. Herein we describe BACE1 inhibitors with limited molecular flexibility and molecular weight that decrease CSF Aβ in vivo, despite efflux. Starting with spirocycle 1a, we explore structure-activity relationships of core changes, P3 moieties, and Asp binding functional groups in order to optimize BACE1 affinity, cathepsin D selectivity, and blood-brain barrier (BBB) penetration. Using wild type guinea pig and rat, we demonstrate a PK/PD relationship between free drug concentrations in the brain and CSF Aβ lowering. Optimization of brain exposure led to the discovery of (R)-50 which reduced CSF Aβ in rodents and in monkey. © 2013 American Chemical Society
Selective Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12) with Activity in a Model of Alzheimer’s Disease
Significant data exists to suggest
that dual leucine zipper kinase (DLK, MAP3K12) is a conserved regulator
of neuronal degeneration following neuronal injury and in chronic
neurodegenerative disease. Consequently, there is considerable interest
in the identification of DLK inhibitors with a profile compatible
with development for these indications. Herein, we use structure-based
drug design combined with a focus on CNS drug-like properties to generate
compounds with superior kinase selectivity and metabolic stability
as compared to previously disclosed DLK inhibitors. These compounds,
exemplified by inhibitor <b>14</b>, retain excellent CNS penetration
and are well tolerated following multiple days of dosing at concentrations
that exceed those required for DLK inhibition in the brain
Selective Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12) with Activity in a Model of Alzheimer’s Disease
Significant data exists to suggest
that dual leucine zipper kinase (DLK, MAP3K12) is a conserved regulator
of neuronal degeneration following neuronal injury and in chronic
neurodegenerative disease. Consequently, there is considerable interest
in the identification of DLK inhibitors with a profile compatible
with development for these indications. Herein, we use structure-based
drug design combined with a focus on CNS drug-like properties to generate
compounds with superior kinase selectivity and metabolic stability
as compared to previously disclosed DLK inhibitors. These compounds,
exemplified by inhibitor <b>14</b>, retain excellent CNS penetration
and are well tolerated following multiple days of dosing at concentrations
that exceed those required for DLK inhibition in the brain
Discovery of a Novel Class of Imidazo[1,2‑<i>a</i>]Pyridines with Potent PDGFR Activity and Oral Bioavailability
The
in silico construction of a PDGFRβ kinase homology model
and ensuing medicinal chemistry guided by molecular modeling, led
to the identification of potent, small molecule inhibitors of PDGFR.
Subsequent exploration of structure–activity relationships
(SAR) led to the incorporation of a constrained secondary amine to
enhance selectivity. Further refinements led to the integration of
a fluorine substituted piperidine, which resulted in significant reduction
of P-glycoprotein (Pgp) mediated efflux and improved bioavailability.
Compound <b>28</b> displayed oral exposure in rodents and had
a pronounced effect in a pharmacokinetic–pharmacodynamic (PKPD)
assay
Discovery of Potent and Selective Pyrazolopyrimidine Janus Kinase 2 Inhibitors
The discovery of somatic Jak2 mutations in patients with
chronic
myeloproliferative neoplasms has led to significant interest in discovering
selective Jak2 inhibitors for use in treating these disorders. A high-throughput
screening effort identified the pyrazoloÂ[1,5-<i>a</i>]Âpyrimidine
scaffold as a potent inhibitor of Jak2. Optimization of lead compounds <b>7a</b>–<b>b</b> and <b>8</b> in this chemical
series for activity against Jak2, selectivity against other Jak family
kinases, and good in vivo pharmacokinetic properties led to the discovery
of <b>7j</b>. In a SET2 xenograft model that is dependent on
Jak2 for growth, <b>7j</b> demonstrated a time-dependent knock-down
of pSTAT5, a downstream target of Jak2
Pyrimidoaminotropanes as Potent, Selective, and Efficacious Small Molecule Kinase Inhibitors of the Mammalian Target of Rapamycin (mTOR)
We
have recently reported a series of tetrahydroquinazoline (THQ)
mTOR inhibitors that produced a clinical candidate <b>1</b> (GDC-0349).
Through insightful design, we hoped to discover and synthesize a new
series of small molecule inhibitors that could attenuate CYP3A4 time-dependent
inhibition commonly observed with the THQ scaffold, maintain or improve
aqueous solubility and oral absorption, reduce free drug clearance,
and selectively increase mTOR potency. Through key in vitro and in
vivo studies, we demonstrate that a pyrimidoaminotropane based core
was able to address each of these goals. This effort culminated in
the discovery of <b>20</b> (GNE-555), a highly potent, selective,
metabolically stable, and efficacious mTOR inhibitor