10 research outputs found
Pharmacokinetics and Absorption of the Anticancer Agents Dasatinib and GDC-0941 under Various Gastric Conditions in Dogs – Reversing the Effect of Elevated Gastric pH with Betaine HCl
Changes in gastric pH can impact
the dissolution and absorption
of compounds presenting pH-dependent solubility. We assessed, in dogs,
the effects of gastric pH-modifying agents on the oral absorption
of two weakly basic anticancer drugs, dasatinib and GDC-0941. We also
tested whether drug-induced hypochlorhydria could be temporarily mitigated
using betaine HCl. Pretreatments with pentagastrin, famotidine, betaine
HCl, or combinations of famotidine and betaine HCl were administered
orally to dogs prior to drug dosing. The gastric pH was measured under
each condition for up to 7 h, and the exposure of the compounds tested
was calculated. The average gastric pH in fasted dogs ranged from
1.45 to 3.03. Pentagastrin or betaine HCl treatments lowered the pH
and reduced its variability between dogs compared to control animals.
In contrast, famotidine treatment maintained gastric pH at values
close to 7 for up to 5 h, while betaine HCl transiently reduced the
pH to approximately 2 in the famotidine-treated dogs. Famotidine pretreatment
lowered GDC-0941 exposure by 5-fold, and decreased dasatinib measurable
concentrations 30-fold, compared to the pentagastrin-treated dogs.
Betaine HCl restored GDC-0941 AUC in famotidine-treated dogs to levels
achieved in control animals, and increased dasatinib AUC to 1.5-fold
that measured in control dogs. The results confirmed the negative
impact of acid-reducing agents on the absorption of weakly basic drugs.
They also suggested that betaine HCl coadministration may be a viable
strategy in humans treated with acid-reducing agents in order to temporarily
reduce gastric pH and restore drug exposure
Design of Selective Benzoxazepin PI3Kδ Inhibitors Through Control of Dihedral Angles
A novel selective benzoxazepin inhibitor
of PI3Kδ has been discovered. Beginning from compound <b>3</b>, an αPI3K inhibitor, we utilized structure-based drug
design and computational analysis of dihedral torsion angles to optimize
for PI3Kδ isoform potency and isoform selectivity. Further medicinal
chemistry optimization of the series led to the identification of <b>24</b>, a highly potent and selective inhibitor of PI3Kδ
Discovery of Clinical Development Candidate GDC-0084, a Brain Penetrant Inhibitor of PI3K and mTOR
Inhibition of phosphoinositide 3-kinase
(PI3K) signaling is an appealing approach to treat brain tumors, especially
glioblastoma multiforme (GBM). We previously disclosed our successful
approach to prospectively design potent and blood–brain barrier
(BBB) penetrating PI3K inhibitors. The previously disclosed molecules
were ultimately deemed not suitable for clinical development due to
projected poor metabolic stability in humans. We, therefore, extended
our studies to identify a BBB penetrating inhibitor of PI3K that was
also projected to be metabolically stable in human. These efforts
required identification of a distinct scaffold for PI3K inhibitors
relative to our previous efforts and ultimately resulted in the identification
of GDC-0084 (<b>16</b>). The discovery and preclinical characterization
of this molecule are described within
Discovery of Aryl Sulfonamides as Isoform-Selective Inhibitors of Na<sub>V</sub>1.7 with Efficacy in Rodent Pain Models
We report on a novel series of aryl
sulfonamides that act as nanomolar
potent, isoform-selective inhibitors of the human sodium channel hNa<sub>V</sub>1.7. The optimization of these inhibitors is described. We
aimed to improve potency against hNa<sub>V</sub>1.7 while minimizing
off-target safety concerns and generated compound <b>3</b>.
This agent displayed significant analgesic effects in rodent models
of acute and inflammatory pain and demonstrated that binding to the
voltage sensor domain 4 site of Na<sub>V</sub>1.7 leads to an analgesic
effect <i>in vivo</i>. Our findings corroborate the importance
of hNa<sub>V</sub>1.7 as a drug target for the treatment of pain
The Rational Design of Selective Benzoxazepin Inhibitors of the α‑Isoform of Phosphoinositide 3‑Kinase Culminating in the Identification of (<i>S</i>)‑2-((2-(1-Isopropyl‑1<i>H</i>‑1,2,4-triazol-5-yl)-5,6-dihydrobenzo[<i>f</i>]imidazo[1,2‑<i>d</i>][1,4]oxazepin-9-yl)oxy)propanamide (GDC-0326)
Inhibitors of the class I phosphoinositide
3-kinase (PI3K) isoform
PI3Kα have received substantial attention for their potential
use in cancer therapy. Despite the particular attraction of targeting
PI3Kα, achieving selectivity for the inhibition of this isoform
has proved challenging. Herein we report the discovery of inhibitors
of PI3Kα that have selectivity over the other class I isoforms
and all other kinases tested. In GDC-0032 (<b>3</b>, taselisib),
we previously minimized inhibition of PI3Kβ relative to the
other class I insoforms. Subsequently, we extended our efforts to
identify PI3Kα-specific inhibitors using PI3Kα crystal
structures to inform the design of benzoxazepin inhibitors with selectivity
for PI3Kα through interactions with a nonconserved residue.
Several molecules selective for PI3Kα relative to the other
class I isoforms, as well as other kinases, were identified. Optimization
of properties related to drug metabolism then culminated in the identification
of the clinical candidate GDC-0326 (<b>4</b>)
Cell Active Hydroxylactam Inhibitors of Human Lactate Dehydrogenase with Oral Bioavailability in Mice
A series
of trisubstituted hydroxylactams was identified as potent
enzymatic and cellular inhibitors of human lactate dehydrogenase A.
Utilizing structure-based design and physical property optimization,
multiple inhibitors were discovered with <10 μM lactate IC<sub>50</sub> in a MiaPaca2 cell line. Optimization of the series led
to <b>29</b>, a potent cell active molecule (MiaPaca2 IC<sub>50</sub> = 0.67 μM) that also possessed good exposure when
dosed orally to mice
Design of Conformationally Constrained Acyl Sulfonamide Isosteres: Identification of <i>N</i>‑([1,2,4]Triazolo[4,3‑<i>a</i>]pyridin-3-yl)methane-sulfonamides as Potent and Selective <i>h</i>Na<sub>V</sub>1.7 Inhibitors for the Treatment of Pain
The
sodium channel Na<sub>V</sub>1.7 has emerged as a promising
target for the treatment of pain based on strong genetic validation
of its role in nociception. In recent years, a number of aryl and
acyl sulfonamides have been reported as potent inhibitors of Na<sub>V</sub>1.7, with high selectivity over the cardiac isoform Na<sub>V</sub>1.5. Herein, we report on the discovery of a novel series
of <i>N</i>-([1,2,4]triazolo[4,3-<i>a</i>]pyridin-3-yl)methanesulfonamides
as selective Na<sub>V</sub>1.7 inhibitors. Starting with the crystal
structure of an acyl sulfonamide, we rationalized that cyclization
to form a fused heterocycle would improve physicochemical properties,
in particular lipophilicity. Our design strategy focused on optimization
of potency for block of Na<sub>V</sub>1.7 and human metabolic stability.
Lead compounds <b>10</b>, <b>13</b> (GNE-131), and <b>25</b> showed excellent potency, good <i>in vitro</i> metabolic stability, and low <i>in vivo</i> clearance
in mouse, rat, and dog. Compound <b>13</b> also displayed excellent
efficacy in a transgenic mouse model of induced pain
Design of Conformationally Constrained Acyl Sulfonamide Isosteres: Identification of <i>N</i>‑([1,2,4]Triazolo[4,3‑<i>a</i>]pyridin-3-yl)methane-sulfonamides as Potent and Selective <i>h</i>Na<sub>V</sub>1.7 Inhibitors for the Treatment of Pain
The
sodium channel Na<sub>V</sub>1.7 has emerged as a promising
target for the treatment of pain based on strong genetic validation
of its role in nociception. In recent years, a number of aryl and
acyl sulfonamides have been reported as potent inhibitors of Na<sub>V</sub>1.7, with high selectivity over the cardiac isoform Na<sub>V</sub>1.5. Herein, we report on the discovery of a novel series
of <i>N</i>-([1,2,4]triazolo[4,3-<i>a</i>]pyridin-3-yl)methanesulfonamides
as selective Na<sub>V</sub>1.7 inhibitors. Starting with the crystal
structure of an acyl sulfonamide, we rationalized that cyclization
to form a fused heterocycle would improve physicochemical properties,
in particular lipophilicity. Our design strategy focused on optimization
of potency for block of Na<sub>V</sub>1.7 and human metabolic stability.
Lead compounds <b>10</b>, <b>13</b> (GNE-131), and <b>25</b> showed excellent potency, good <i>in vitro</i> metabolic stability, and low <i>in vivo</i> clearance
in mouse, rat, and dog. Compound <b>13</b> also displayed excellent
efficacy in a transgenic mouse model of induced pain
Design of Conformationally Constrained Acyl Sulfonamide Isosteres: Identification of <i>N</i>‑([1,2,4]Triazolo[4,3‑<i>a</i>]pyridin-3-yl)methane-sulfonamides as Potent and Selective <i>h</i>Na<sub>V</sub>1.7 Inhibitors for the Treatment of Pain
The
sodium channel Na<sub>V</sub>1.7 has emerged as a promising
target for the treatment of pain based on strong genetic validation
of its role in nociception. In recent years, a number of aryl and
acyl sulfonamides have been reported as potent inhibitors of Na<sub>V</sub>1.7, with high selectivity over the cardiac isoform Na<sub>V</sub>1.5. Herein, we report on the discovery of a novel series
of <i>N</i>-([1,2,4]triazolo[4,3-<i>a</i>]pyridin-3-yl)methanesulfonamides
as selective Na<sub>V</sub>1.7 inhibitors. Starting with the crystal
structure of an acyl sulfonamide, we rationalized that cyclization
to form a fused heterocycle would improve physicochemical properties,
in particular lipophilicity. Our design strategy focused on optimization
of potency for block of Na<sub>V</sub>1.7 and human metabolic stability.
Lead compounds <b>10</b>, <b>13</b> (GNE-131), and <b>25</b> showed excellent potency, good <i>in vitro</i> metabolic stability, and low <i>in vivo</i> clearance
in mouse, rat, and dog. Compound <b>13</b> also displayed excellent
efficacy in a transgenic mouse model of induced pain
Discovery of Novel PI3-Kinase δ Specific Inhibitors for the Treatment of Rheumatoid Arthritis: Taming CYP3A4 Time-Dependent Inhibition
PI3Kδ is a lipid kinase and a member of a larger
family of enzymes, PI3K class IA(α, β, δ) and IB
(γ), which catalyze the phosphorylation of PIP2 to PIP3. PI3Kδ
is mainly expressed in leukocytes, where it plays a critical, nonredundant
role in B cell receptor mediated signaling and provides an attractive
opportunity to treat diseases where B cell activity is essential,
e.g., rheumatoid arthritis. We report the discovery of novel, potent,
and selective PI3Kδ inhibitors and describe a structural hypothesis
for isoform (α, β, γ) selectivity gained from interactions
in the affinity pocket. The critical component of our initial pharmacophore
for isoform selectivity was strongly associated with CYP3A4 time-dependent
inhibition (TDI). We describe a variety of strategies and methods
for monitoring and attenuating TDI. Ultimately, a structure-based
design approach was employed to identify a suitable structural replacement
for further optimization