5 research outputs found
Diamine Derivatives as Novel Small-Molecule, Potent, and Subtype-Selective Somatostatin SST3 Receptor Agonists
A novel
class of small-molecule, highly potent, and subtype-selective somatostatin
SST3 agonists was discovered through modification of a SST3 antagonist. As an example, (1<i>R</i>,2<i>S</i>)-<b>9</b> demonstrated not only
potent in vitro SST3 agonist activity but also in vivo SST3 agonist
activity in a mouse oral glucose tolerance test (OGTT). These agonists
may be useful reagents for studying the physiological roles of the
SST3 receptor and may potentially be useful as therapeutic agents
Discovery of a Potent and Selective DGAT1 Inhibitor with a Piperidinyl-oxy-cyclohexanecarboxylic Acid Moiety
We report the discovery of a novel
series of DGAT1 inhibitors in
the benzimidazole class with a piperdinyl-oxy-cyclohexanecarboxylic
acid moiety. This novel series possesses significantly improved selectivity
against the A<sub>2A</sub> receptor, no ACAT1 off-target activity
at 10 μM, and higher aqueous solubility and free fraction in
plasma as compared to the previously reported pyridyl-oxy-cyclohexanecarboxylic
acid series. In particular, <b>5B</b> was shown to possess an
excellent selectivity profile by screening it against a panel of more
than 100 biological targets. Compound <b>5B</b> significantly
reduces lipid excursion in LTT in mouse and rat, demonstrates DGAT1
mediated reduction of food intake and body weight in mice, is negative
in a 3-strain Ames test, and appears to distribute preferentially
in the liver and the intestine in mice. We believe this lead series
possesses significant potential to identify optimized compounds for
clinical development
Investigation of Cardiovascular Effects of Tetrahydro-β-carboline sstr3 antagonists
Antagonism
of somatostatin subtype receptor 3 (sstr3) has emerged
as a potential treatment of Type 2 diabetes. Unfortunately, the development
of our first preclinical candidate, MK-4256, was discontinued due
to a dose-dependent QTc (QT interval corrected for heart rate) prolongation
observed in a conscious cardiovascular (CV) dog model. As the fate
of the entire program rested on resolving this issue, it was imperative
to determine whether the observed QTc prolongation was associated
with hERG channel (the protein encoded by the human Ether-à-go-go-Related
Gene) binding or was mechanism-based as a result of antagonizing sstr3.
We investigated a structural series containing carboxylic acids to
reduce the putative hERG off-target activity. A key tool compound, <b>3A</b>, was identified from this SAR effort. As a potent sstr3
antagonist, <b>3A</b> was shown to reduce glucose excursion
in a mouse oGTT assay. Consistent with its minimal hERG activity from
in vitro assays, <b>3A</b> elicited little to no effect in an
anesthetized, vagus-intact CV dog model at high plasma drug levels.
These results afforded the critical conclusion that sstr3 antagonism
is not responsible for the QTc effects and therefore cleared a path
for the program to progress
Discovery of MK-1421, a Potent, Selective sstr3 Antagonist, as a Development Candidate for Type 2 Diabetes
The imidazolyl-tetrahydro-β-carboline
class of sstr3 antagonists
have demonstrated efficacy in a murine model of glucose excursion
and may have potential as a treatment for type 2 diabetes. The first
candidate in this class caused unacceptable QTc interval prolongation
in oral, telemetrized cardiovascular (CV) dogs. Herein, we describe
our efforts to identify an acceptable candidate without CV effects.
These efforts resulted in the identification of (1<i>R</i>,3<i>R</i>)-3-(4-(5-fluoropyridin-2-yl)-1<i>H</i>-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-1-(3-methyl-1,3,4-oxadiazol-3<i>H</i>-2-one-5-yl)-2,3,4,9-tetrahydro-1<i>H</i>-β-carboline
(<b>17e</b>, MK-1421)
The Discovery of MK-4256, a Potent SSTR3 Antagonist as a Potential Treatment of Type 2 Diabetes
A structure–activity relationship study of the
imidazolyl-β-tetrahydrocarboline
series identified MK-4256 as a potent, selective SSTR3 antagonist,
which demonstrated superior efficacy in a mouse oGTT model. MK-4256
reduced glucose excursion in a dose-dependent fashion with maximal
efficacy achieved at doses as low as 0.03 mg/kg po. As compared with
glipizide, MK-4256 showed a minimal hypoglycemia risk in mice