5 research outputs found
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
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
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
Maximizing Diversity from a Kinase Screen: Identification of Novel and Selective pan-Trk Inhibitors for Chronic Pain
We
have identified several series of small molecule inhibitors
of TrkA with unique binding modes. The starting leads were chosen
to maximize the structural and binding mode diversity derived from
a high throughput screen of our internal compound collection. These
leads were optimized for potency and selectivity employing a structure
based drug design approach adhering to the principles of ligand efficiency
to maximize binding affinity without overly relying on lipophilic
interactions. This endeavor resulted in the identification of several
small molecule pan-Trk inhibitor series that exhibit high selectivity
for TrkA/B/C versus a diverse panel of kinases. We have also demonstrated
efficacy in both inflammatory and neuropathic pain models upon oral
dosing. Herein we describe the identification process, hit-to-lead
progression, and binding profiles of these selective pan-Trk kinase
inhibitors
Discovery of a 3‑(4-Pyrimidinyl) Indazole (MLi-2), an Orally Available and Selective Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor that Reduces Brain Kinase Activity
Leucine-rich repeat
kinase 2 (LRRK2) is a large, multidomain protein
which contains a kinase domain and GTPase domain among other regions.
Individuals possessing gain of function mutations in the kinase domain
such as the most prevalent G2019S mutation have been associated with
an increased risk for the development of Parkinson’s disease
(PD). Given this genetic validation for inhibition of LRRK2 kinase
activity as a potential means of affecting disease progression, our
team set out to develop LRRK2 inhibitors to test this hypothesis.
A high throughput screen of our compound collection afforded a number
of promising indazole leads which were truncated in order to identify
a minimum pharmacophore. Further optimization of these indazoles led
to the development of MLi-2 (<b>1</b>): a potent, highly selective,
orally available, brain-penetrant inhibitor of LRRK2