4 research outputs found
Discovery of Alternative Binding Poses through Fragment-Based Identification of DHODH Inhibitors
Dihydroorotate dehydrogenase (DHODH) is a mitochondrial
enzyme
that affects many aspects essential to cell proliferation and survival.
Recently, DHODH has been identified as a potential target for acute
myeloid leukemia therapy. Herein, we describe the identification of
potent DHODH inhibitors through a scaffold hopping approach emanating
from a fragment screen followed by structure-based drug design to
further improve the overall profile and reveal an unexpected novel
binding mode. Additionally, these compounds had low P-gp efflux ratios,
allowing for applications where exposure to the brain would be required
Discovery of Naphthyl-Fused 5‑Membered Lactams as a New Class of M<sub>1</sub> Positive Allosteric Modulators
Selective activation of the M<sub>1</sub> muscarinic receptor via
positive allosteric modulation represents an original approach to
treat the cognitive decline in patients with Alzheimer’s disease.
A series of naphthyl-fused 5-membered lactams were identified as a
new class of M<sub>1</sub> positive allosteric modulators and were
found to possess good potency and in vivo efficacy
Identification of Amides as Carboxylic Acid Surrogates for Quinolizidinone-Based M<sub>1</sub> Positive Allosteric Modulators
Selective activation of the M<sub>1</sub> muscarinic
receptor via positive allosteric modulation represents an approach
to treat the cognitive decline in patients with Alzheimer's disease.
A series of amides were examined as a replacement for the carboxylic
acid moiety in a class of quinolizidinone carboxylic acid M<sub>1</sub> muscarinic receptor positive allosteric modulators, and leading
pyran <b>4o</b> and cyclohexane <b>5c</b> were found to
possess good potency and in vivo efficacy
MK-7622: A First-in-Class M<sub>1</sub> Positive Allosteric Modulator Development Candidate
Identification
of ligands that selectively activate the M<sub>1</sub> muscarinic
signaling pathway has been sought for decades to treat
a range of neurological and cognitive disorders. Herein, we describe
the optimization efforts focused on addressing key physicochemical
and safety properties, ultimately leading to the clinical candidate
MK-7622, a highly selective positive allosteric modulator of the M<sub>1</sub> muscarinic receptor that has entered Phase II studies in
patients with Alzheimer’s disease