9 research outputs found
Radical and Concerted Mechanisms in Oxidations of Amines, Sulfides, and Alkenes by Peroxynitrite, Peroxynitrous Acid, and the Peroxynitrite−CO 2
Stereoselectivities of Nucleophilic Additions to Cycloheptanones. Experimental and Theoretical Studies and General Purpose Force Field for the Prediction of Nucleophilic Addition Stereoselectivities
Identification of a New Class of Glucokinase Activators through Structure-Based Design
Glucose flux through glucokinase
(GK) controls insulin release
from the pancreas in response to high glucose concentrations. Glucose
flux through GK also contributes to reducing hepatic glucose output.
Because many individuals with type 2 diabetes appear to have an inadequacy
or defect in one or both of these processes, compounds that can activate
GK may serve as effective treatments for type 2 diabetes. Herein we
report the identification and initial optimization of a novel series
of allosteric glucokinase activators (GKAs). We discovered an initial
thiazolylamino pyridine-based hit that was optimized using a structure-based
design strategy and identified <b>26</b> as an early lead. Compound <b>26</b> demonstrated a good balance of in vitro potency and enzyme
kinetic parameters and demonstrated blood glucose reductions in oral
glucose tolerance tests in both C57BL/6J mice and high-fat fed Zucker
diabetic fatty rats
Discovery of 2‑Pyridylureas as Glucokinase Activators
Glucokinase
(GK) is the rate-limiting step for insulin release
from the pancreas in response to high levels of glucose. Flux through
GK also contributes to reducing hepatic glucose output. Since many
individuals with type 2 diabetes appear to have an inadequacy or defect
in one or both of these processes, identifying compounds that can
allosterically activate GK may address this issue. Herein we report
the identification and initial optimization of a novel series of glucokinase
activators (GKAs). Optimization led to the identification of <b>33</b> as a compound that displayed activity in an oral glucose
tolerance test (OGTT) in normal and diabetic mice
Preclinical Characteristics of the Hepatitis C Virus NS3/4A Protease Inhibitor ITMN-191 (R7227) â–¿ â€
Future treatments for chronic hepatitis C virus (HCV) infection are likely to include agents that target viral components directly. Here, the preclinical characteristics of ITMN-191, a peptidomimetic inhibitor of the NS3/4A protease of HCV, are described. ITMN-191 inhibited a reference genotype 1 NS3/4A protein in a time-dependent fashion, a hallmark of an inhibitor with a two-step binding mechanism and a low dissociation rate. Under preequilibrium conditions, 290 pM ITMN-191 half-maximally inhibited the reference NS3/4A protease, but a 35,000-fold-higher concentration did not appreciably inhibit a panel of 79 proteases, ion channels, transporters, and cell surface receptors. Subnanomolar biochemical potency was maintained against NS3/4A derived from HCV genotypes 4, 5, and 6, while single-digit nanomolar potency was observed against NS3/4A from genotypes 2b and 3a. Dilution of a preformed enzyme inhibitor complex indicated ITMN-191 remained bound to and inhibited NS3/4A for more than 5 h after its initial association. In cell-based potency assays, half-maximal reduction of genotype 1b HCV replicon RNA was afforded by 1.8 nM; 45 nM eliminated the HCV replicon from cells. Peginterferon alfa-2a displayed a significant degree of antiviral synergy with ITMN-191 and reduced the concentration of ITMN-191 required for HCV replicon elimination. A 30-mg/kg of body weight oral dose administered to rats or monkeys yielded liver concentrations 12 h after dosing that exceeded the ITMN-191 concentration required to eliminate replicon RNA from cells. These preclinical characteristics compare favorably to those of other inhibitors of NS3/4A in clinical development and therefore support the clinical investigation of ITMN-191 for the treatment of chronic hepatitis C
Discovery of Danoprevir (ITMN-191/R7227), a Highly Selective and Potent Inhibitor of Hepatitis C Virus (HCV) NS3/4A Protease
HCV serine protease NS3 represents
an attractive drug target because it is not only essential for viral
replication but also implicated in the viral evasion of the host immune
response pathway through direct cleavage of key proteins in the human
innate immune system. Through structure-based drug design and optimization,
macrocyclic peptidomimetic molecules bearing both a lipophilic P2
isoindoline carbamate and a P1/P1′ acylsulfonamide/acylsulfamide
carboxylic acid bioisostere were prepared that possessed subnanomolar
potency against the NS3 protease in a subgenomic replicon-based cellular
assay (Huh-7). Danoprevir (compound <b>49</b>) was selected
as the clinical development candidate for its favorable potency profile
across multiple HCV genotypes and key mutant strains and for its good
in vitro ADME profiles and in vivo target tissue (liver) exposures
across multiple animal species. X-ray crystallographic studies elucidated
several key features in the binding of danoprevir to HCV NS3 protease
and proved invaluable to our iterative structure-based design strategy
Novel Series of Potent Glucokinase Activators Leading to the Discovery of AM-2394
Glucokinase
(GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate.
We present the structure–activity relationships leading to
the discovery of <b>AM-2394</b>, a structurally distinct GKA. <b>AM-2394</b> activates GK with an EC<sub>50</sub> of 60 nM, increases
the affinity of GK for glucose by approximately 10-fold, exhibits
moderate clearance and good oral bioavailability in multiple animal
models, and lowers glucose excursion following an oral glucose tolerance
test in an <i>ob/ob</i> mouse model of diabetes
C5-Alkyl-2-methylurea-Substituted Pyridines as a New Class of Glucokinase Activators
Glucokinase
(GK) activators represent a class of type 2 diabetes therapeutics
actively pursued due to the central role that GK plays in regulating
glucose homeostasis. Herein we report a novel C5-alkyl-2-methylurea-substituted
pyridine series of GK activators derived from our previously reported
thiazolylamino pyridine series. Our efforts in optimizing potency,
enzyme kinetic properties, and metabolic stability led to the identification
of compound <b>26</b> (<b>AM-9514</b>). This analogue
showed a favorable combination of <i>in vitro</i> potency,
enzyme kinetic properties, acceptable pharmacokinetic profiles in
preclinical species, and robust efficacy in a rodent PD model