14 research outputs found
Facile Modulation of Antibody Fucosylation with Small Molecule Fucostatin Inhibitors and Cocrystal Structure with GDP-Mannose 4,6-Dehydratase
The efficacy of therapeutic antibodies
that induce antibody-dependent cellular cytotoxicity can be improved
by reduced fucosylation. Consequently, fucosylation is a critical
product attribute of monoclonal antibodies produced as protein therapeutics.
Small molecule fucosylation inhibitors have also shown promise as
potential therapeutics in animal models of tumors, arthritis, and
sickle cell disease. Potent small molecule metabolic inhibitors of
cellular protein fucosylation, 6,6,6-trifluorofucose per-<i>O</i>-acetate and 6,6,6-trifluorofucose (fucostatin I), were identified
that reduces the fucosylation of recombinantly expressed antibodies
in cell culture in a concentration-dependent fashion enabling the
controlled modulation of protein fucosylation levels. 6,6,6-Trifluorofucose
binds at an allosteric site of GDP-mannose 4,6-dehydratase (GMD) as
revealed for the first time by the X-ray cocrystal structure of a
bound allosteric GMD inhibitor. 6,6,6-Trifluorofucose was found to
be incorporated in place of fucose at low levels (<1%) in the glycans
of recombinantly expressed antibodies. A fucose-1-phosphonate analog,
fucostatin II, was designed that inhibits fucosylation with no incorporation
into antibody glycans, allowing the production of afucosylated antibodies
in which the incorporation of non-native sugar is <i>completely
absent</i>î—¸a key advantage in the production of therapeutic
antibodies, especially biosimilar antibodies. Inhibitor structure–activity
relationships, identification of cellular and inhibitor metabolites
in inhibitor-treated cells, fucose competition studies, and the production
of recombinant antibodies with varying levels of fucosylation are
described
Discovery, Optimization, and in Vivo Evaluation of Benzimidazole Derivatives AM-8508 and AM-9635 as Potent and Selective PI3Kδ Inhibitors
Lead
optimization efforts resulted in the discovery of two potent,
selective, and orally bioavailable PI3Kδ inhibitors, <b>1</b> (AM-8508) and <b>2</b> (AM-9635), with good pharmacokinetic
properties. The compounds inhibit B cell receptor (BCR)-mediated AKT
phosphorylation (pAKT) in PI3Kδ-dependent in vitro cell based
assays. These compounds which share a benzimidazole bicycle are effective
when administered in vivo at unbound concentrations consistent with
their in vitro cell potency as a consequence of improved unbound drug
concentration with lower unbound clearance. Furthermore, the compounds
demonstrated efficacy in a Keyhole Limpet Hemocyanin (KLH) study in
rats, where the blockade of PI3Kδ activity by inbibitors <b>1</b> and <b>2</b> led to effective inhibition of antigen-specific
IgG and IgM formation after immunization with KLH
Structure–Activity Relationships of Phosphoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitors: Investigations of Various 6,5-Heterocycles to Improve Metabolic Stability
Discovery and in Vivo Evaluation of the Potent and Selective PI3Kδ Inhibitors 2‑((1<i>S</i>)‑1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro‑<i>N</i>‑methyl-3-(2-pyridinyl)-4-quinolinecarboxamide (AM-0687) and 2‑((1<i>S</i>)‑1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-5-fluoro‑<i>N</i>‑methyl-3-(2-pyridinyl)-4-quinolinecarboxamide (AM-1430)
Optimization
of the potency and pharmacokinetic profile of 2,3,4-trisubstituted
quinoline, <b>4</b>, led to the discovery of two potent, selective,
and orally bioavailable PI3Kδ inhibitors, <b>6a</b> (AM-0687)
and <b>7</b> (AM-1430). On the basis of their improved profile,
these analogs were selected for in vivo pharmacodynamic (PD) and efficacy
experiments in animal models of inflammation. The in vivo PD studies,
which were carried out in a mouse pAKT inhibition animal model, confirmed
the observed potency of <b>6a</b> and <b>7</b> in biochemical
and cellular assays. Efficacy experiments in a keyhole limpet hemocyanin
model in rats demonstrated that administration of either <b>6a</b> or <b>7</b> resulted in a strong dose-dependent reduction
of IgG and IgM specific antibodies. The excellent in vitro and in
vivo profiles of these analogs make them suitable for further development
Correction to Selective Class I Phosphoinositide 3-Kinase Inhibitors: Optimization of a Series of Pyridyltriazines Leading to the Identification of a Clinical Candidate, AMG 511
Structure-Based Design of a Novel Series of Potent, Selective Inhibitors of the Class I Phosphatidylinositol 3-Kinases
A highly selective series of inhibitors of the class
I phosphatidylinositol
3-kinases (PI3Ks) has been designed and synthesized. Starting from
the dual PI3K/mTOR inhibitor <b>5</b>, a structure-based approach
was used to improve potency and selectivity, resulting in the identification
of <b>54</b> as a potent inhibitor of the class I PI3Ks with
excellent selectivity over mTOR, related phosphatidylinositol kinases,
and a broad panel of protein kinases. Compound <b>54</b> demonstrated
a robust PD–PK relationship inhibiting the PI3K/Akt pathway
in vivo in a mouse model, and it potently inhibited tumor growth in
a U-87 MG xenograft model with an activated PI3K/Akt pathway
A Potent and Orally Efficacious, Hydroxyethylamine-Based Inhibitor of β-Secretase
β-Secretase inhibitors are potentially disease-modifying
treatments for Alzheimer's disease. Previous efforts in our laboratory
have resulted in hydroxyethylamine-derived inhibitors such as <b>1</b> with low nanomolar potency against β-site amyloid
precursor protein cleaving enzyme (BACE). When dosed intravenously,
compound <b>1</b> was also shown to significantly reduce Aβ<sub>40</sub> levels in plasma, brain, and cerebral spinal fluid. Herein,
we report further optimizations that led to the discovery of inhibitor <b>16</b> as a novel, potent, and orally efficacious BACE inhibitor
Discovery and in Vivo Evaluation of (<i>S</i>)‑<i>N</i>‑(1-(7-Fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)‑9<i>H</i>‑purin-6-amine (AMG319) and Related PI3Kδ Inhibitors for Inflammation and Autoimmune Disease
The development and optimization
of a series of quinolinylpurines
as potent and selective PI3Kδ kinase inhibitors with excellent
physicochemical properties are described. This medicinal chemistry
effort led to the identification of <b>1</b> (AMG319), a compound
with an IC<sub>50</sub> of 16 nM in a human whole blood assay (HWB),
excellent selectivity over a large panel of protein kinases, and a
high level of in vivo efficacy as measured by two rodent disease models
of inflammation
Selective Class I Phosphoinositide 3‑Kinase Inhibitors: Optimization of a Series of Pyridyltriazines Leading to the Identification of a Clinical Candidate, AMG 511
The phosphoinositide 3-kinase family catalyzes the phosphorylation
of phosphatidylinositol-4,5-diphosphate to phosphatidylinositol-3,4,5-triphosphate,
a secondary messenger which plays a critical role in important cellular
functions such as metabolism, cell growth, and cell survival. Our
efforts to identify potent, efficacious, and orally available phosphatidylinositol
3-kinase (PI3K) inhibitors as potential cancer therapeutics have resulted
in the discovery of 4-(2-((6-methoxypyridin-3-yl)Âamino)-5-((4-(methylsulfonyl)Âpiperazin-1-yl)Âmethyl)Âpyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine
(<b>1</b>). In this paper, we describe the optimization of compound <b>1</b>, which led to the design and synthesis of pyridyltriazine <b>31</b>, a potent pan inhibitor of class I PI3Ks with a superior
pharmacokinetic profile. Compound <b>31</b> was shown to potently
block the targeted PI3K pathway in a mouse liver pharmacodynamic model
and inhibit tumor growth in a U87 malignant glioma glioblastoma xenograft
model. On the basis of its excellent in vivo efficacy and pharmacokinetic
profile, compound <b>31</b> was selected for further evaluation
as a clinical candidate and was designated AMG 511
Design and Preparation of a Potent Series of Hydroxyethylamine Containing β-Secretase Inhibitors That Demonstrate Robust Reduction of Central β-Amyloid
A series of potent hydroxyethyl amine (HEA) derived inhibitors
of β-site APP cleaving enzyme (BACE1) was optimized to address
suboptimal pharmacokinetics and poor CNS partitioning. This work identified
a series of benzodioxolane analogues that possessed improved metabolic
stability and increased oral bioavailability. Subsequent efforts focused
on improving CNS exposure by limiting susceptibility to Pgp-mediated
efflux and identified an inhibitor which demonstrated robust and sustained
reduction of CNS β-amyloid (Aβ) in Sprague–Dawley
rats following oral administration