7 research outputs found
Discovery of a Potent Dihydrooxadiazole Series of Non-ATP-Competitive MK2 (MAPKAPK2) Inhibitors
Inhibition of MK2 has been shown to offer advantages
over that of p38 MAPK in the development of cures for inflammatory
diseases such as arthritis. P38 MAPK knockout in mice was lethal,
whereas MK2-null mice demonstrated strong inhibition of disease progression
in collagen-induced arthritis and appeared normal and viable. However,
it is challenging to develop ATP-competitive MK2 inhibitors due to
high ATP binding affinity to the kinase. Non-ATP-competitive MK2 inhibitors
interact and bind to the kinase in a mode independent of ATP concentration,
which could provide better selectivity and cellular potency. Therefore,
it is desirable to identify non-ATP-competitive MK2 inhibitors. Through
structure optimization of lead compound <b>1</b>, a novel series
of dihydrooxadiazoles was discovered. Additional structure–activity
relationship (SAR) study of this series led to the identification of compound <b>38</b> as a non-ATP-competitive MK2 inhibitor with potent enzymatic
activity and good cellular potency. The SAR, synthesis, and biological
data of dihydrooxadiazole series are discussed
Ligand-Dependent Site-Selective Suzuki Cross-Coupling of 3,5-Dichloropyridazines
General
methods for the highly site-selective Suzuki monocoupling
of 3,5-dichloropyridazines have been discovered. By changing the ligand
employed, the preferred coupling site can be switched from the 3-position
to the 5-position, typically considered the less reactive C–X
bond. These conditions are applicable to the coupling of a wide variety
of aryl-, heteroaryl-, and vinylboronic acids with high selectivities,
thus enabling the rapid construction of diverse arrays of diarylpyradazines
in a modular fashion
Discovery of a Tetrahydrobenzisoxazole Series of γ‑Secretase Modulators
The
design and synthesis of a new series of tetrahydrobenzisoxazoles
as modulators of γ-secretase activity and their structure–activity
relationship (SAR) will be detailed. Several compounds are active
γ-secretase modulators (GSMs) with good to excellent selectivity
for the reduction of Aβ<sub>42</sub> in the cellular assay.
Compound <b>14a</b> was tested <i>in vivo</i> in a
nontransgenic rat model and was found to significantly reduce Aβ<sub>42</sub> in the CNS compartment compared to vehicle-treated animals
(up to 58% reduction of cerebrospinal fluid Aβ<sub>42</sub> as
measured 3 h after an acute oral dosing at 30 mg/kg)
Discovery of a Potent Thiadiazole Class of Histamine H<sub>3</sub> Receptor Antagonist for the Treatment of Diabetes
A series of novel 2-piperidinopiperidine thiadiazoles
were synthesized
and evaluated as new leads of histamine H<sub>3</sub> receptor antagonists.
The 4-(5-([1,4′-bipiperidin]-1′-yl)-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)Âmorpholine
(<b>5u</b>) displayed excellent potency and ex vivo receptor
occupancy. Compound <b>5u</b> was also evaluated in vivo for
antidiabetic efficacy in STZ diet-induced obesity type 2 diabetic
mice for 2 or 12 days. Non-fasting glucose levels were significantly
reduced as compared with vehicle-treated mice. In addition, <b>5u</b> dose dependently blocked the increase of HbA<sub>1c</sub> after 12 days of treatment
Synthesis and SAR Studies of Fused Oxadiazines as γ‑Secretase Modulators for Treatment of Alzheimer's Disease
Fused oxadiazines (<b>3</b>) were discovered as
selective and orally bioavailable γ-secretase modulators (GSMs)
based on the structural framework of oxadiazoline GSMs. Although structurally
related, initial modifications showed that structure–activity
relationships (SARs) did not translate from the oxadiazoline to the
oxadiazine series. Subsequent SAR studies on modifications at the
C3 and C4 positions of the fused oxadiazine core helped to identify
GSMs such as compounds <b>8r</b> and <b>8s</b> that were
highly efficacious in vitro and in vivo in a number of animal models
with highly desirable physical and pharmacological properties. Further
improvements of in vitro activity and selectivity were achieved by
the preparation of fused morpholine oxadiazines. The shift in specificity
of APP cleavage rather than a reduction in overall γ-secretase
activity and the lack of changes in substrate accumulation and Notch
processing as observed in the animal studies of compound <b>8s</b> confirm that the oxadiazine series of compounds are potent GSMs
Discovery of SCH 900271, a Potent Nicotinic Acid Receptor Agonist for the Treatment of Dyslipidemia
Structure-guided optimization of a series of C-5 alkyl
substituents
led to the discovery of a potent nicotinic acid receptor agonist SCH
900271 (<b>33</b>) with an EC<sub>50</sub> of 2 nM in the hu-GPR109a
assay. Compound <b>33</b> demonstrated good oral bioavailability
in all species. Compound <b>33</b> exhibited dose-dependent
inhibition of plasma free fatty acid (FFA) with 50% FFA reduction
at 1.0 mg/kg in fasted male beagle dogs. Compound <b>33</b> had
no overt signs of flushing at doses up to 10 mg/kg with an improved
therapeutic window to flushing as compared to nicotinic acid. Compound <b>33</b> was evaluated in human clinical trials
Discovery of MK-8318, a Potent and Selective CRTh2 Receptor Antagonist for the Treatment of Asthma
A novel series of
tricyclic tetrahydroquinolines were identified
as potent and selective CRTh2 receptor antagonists. The agonism and
antagonism switch was achieved through structure-based drug design
(SBDD) using a CRTh2 receptor homologue model. The challenge of very
low exposures in pharmacokinetic studies was overcome by exhaustive
medicinal chemistry lead optimization through focused SAR studies
on the tricyclic core. Further optimization resulted in the identification
of the preclinical candidate 4-(cyclopropylÂ((3<i>aS</i>,9<i>R</i>,9<i>aR</i>)-7-fluoro-4-(4-(trifluoromethoxy)Âbenzoyl)-2,3,3<i>a</i>,4,9,9<i>a</i>-hexahydro-1<i>H</i>-cyclopentaÂ[<i>b</i>]Âquinolin-9-yl)Âamino)-4-oxobutanoic acid (<b>15c</b>, <b>MK-8318</b>) with potent and selective CRTh2 antagonist
activity and a favorable PK profile suitable for once daily oral dosing
for potential treatment of asthma