8 research outputs found
Structure-Based Design of Novel Class II c-Met Inhibitors: 1. Identification of Pyrazolone-Based Derivatives
Deregulation of c-Met receptor tyrosine kinase activity
leads to
tumorigenesis and metastasis in animal models. More importantly, the
identification of activating mutations in c-Met, as well as <i>MET</i> gene amplification in human cancers, points to c-Met
as an important target for cancer therapy. We have previously described
two classes of c-Met kinase inhibitors (class I and class II) that
differ in their binding modes and selectivity profiles. The class
II inhibitors tend to have activities on multiple kinases. Knowledge
of the binding mode of these molecules in the c-Met protein led to
the design and evaluation of several new class II c-Met inhibitors
that utilize various 5-membered cyclic carboxamides to conformationally
restrain key pharmacophoric groups within the molecule. These investigations
resulted in the identification of a potent and novel class of pyrazolone
c-Met inhibitors with good in vivo activity
Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 5. A Novel Aryl Sulfone Series, Optimization Through Conformational Analysis
The
glucokinase–glucokinase regulatory protein (GK-GKRP)
complex plays an important role in controlling glucose homeostasis
in the liver. We have recently disclosed a series of arylpiperazines
as in vitro and in vivo disruptors of the GK-GKRP complex with efficacy
in rodent models of type 2 diabetes mellitus (T2DM). Herein, we describe
a new class of aryl sulfones as disruptors of the GK-GKRP complex,
where the central piperazine scaffold has been replaced by an aromatic
group. Conformational analysis and exploration of the structure–activity
relationships of this new class of compounds led to the identification
of potent GK-GKRP disruptors. Further optimization of this novel series
delivered thiazole sulfone <b>93</b>, which was able to disrupt
the GK-GKRP interaction in vitro and in vivo and, by doing so, increases
cytoplasmic levels of unbound GK
Structure-Based Design of Novel Class II c-Met Inhibitors: 2. SAR and Kinase Selectivity Profiles of the Pyrazolone Series
As part of our effort toward developing an effective
therapeutic agent for c-Met-dependent tumors, a pyrazolone-based class
II c-Met inhibitor, <i>N</i>-(4-((6,7-dimethoxyquinolin-4-yl)Âoxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1<i>H</i>-pyrazole-4-carboxamide (<b>1</b>), was identified.
Knowledge of the binding mode of this molecule in both c-Met and VEGFR-2
proteins led to a novel strategy for designing more selective analogues
of <b>1</b>. Along with detailed SAR information, we demonstrate
that the low kinase selectivity associated with class II c-Met inhibitors
can be improved significantly. This work resulted in the discovery
of potent c-Met inhibitors with improved selectivity profiles over
VEGFR-2 and IGF-1R that could serve as useful tools to probe the relationship
between kinase selectivity and in vivo efficacy in tumor xenograft
models. Compound <b>59e</b> (AMG 458) was ultimately advanced
into preclinical safety studies
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%)
Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 2. Leveraging Structure-Based Drug Design to Identify Analogues with Improved Pharmacokinetic Profiles
In
the previous report, we described the
discovery and optimization of novel small molecule disruptors of the
GK-GKRP interaction culminating in the identification of <b>1</b> (AMG-1694). Although this analogue possessed excellent in vitro
potency and was a useful tool compound in initial proof-of-concept
experiments, high metabolic turnover limited its advancement. Guided
by a combination of metabolite identification and structure-based
design, we have successfully discovered a potent and metabolically
stable GK-GKRP disruptor (<b>27</b>, AMG-3969). When administered
to <i>db</i>/<i>db</i> mice, this compound demonstrated
a robust pharmacodynamic response (GK translocation) as well as statistically
significant dose-dependent reductions in fed blood glucose levels
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
Discovery and Structure-Guided Optimization of Diarylmethanesulfonamide Disrupters of Glucokinase–Glucokinase Regulatory Protein (GK–GKRP) Binding: Strategic Use of a N → S (n<sub>N</sub> → σ*<sub>S–X</sub>) Interaction for Conformational Constraint
The HTS-based discovery and structure-guided
optimization of a
novel series of GKRP-selective GK–GKRP disrupters are revealed.
DiarylmethaneÂsulfonamide hit <b>6</b> (hGK–hGKRP
IC<sub>50</sub> = 1.2 μM) was optimized to lead compound <b>32</b> (AMG-0696; hGK–hGKRP IC<sub>50</sub> = 0.0038 μM).
A stabilizing interaction between a nitrogen atom lone pair and an
aromatic sulfur system (n<sub>N</sub> → σ*<sub>S–X</sub>) in <b>32</b> was exploited to conformationally constrain
a biaryl linkage and allow contact with key residues in GKRP. Lead
compound <b>32</b> was shown to induce GK translocation from
the nucleus to the cytoplasm in rats (IHC score = 0; 10 mg/kg po,
6 h) and blood glucose reduction in mice (POC = −45%; 100 mg/kg
po, 3 h). X-ray analyses of <b>32</b> and several precursors
bound to GKRP were also obtained. This novel disrupter of GK–GKRP
binding enables further exploration of GKRP as a potential therapeutic
target for type II diabetes and highlights the value of exploiting
unconventional nonbonded interactions in drug design
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