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Bioorg Med Chem Lett. 2016 Jan 1;26(1):126-32. doi: 10.1016/j.bmcl.2015.11.013. Epub 2015 Nov 10.

Discovery of pyrazolopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia.

Author information

1
Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
2
Basic Pharmaceutical Sciences, Merck Research Laboratories, West Point, PA 19486, United States.
3
Imaging, Merck Research Laboratories, West Point, PA 19486, United States.
4
In Vivo Pharmacology, Merck Research Laboratories, West Point, PA 19486, United States.
5
Neuroscience, Merck Research Laboratories, West Point, PA 19486, United States.
6
Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, United States.
7
Discovery Process Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
8
Chemistry Modeling and Informatics, Merck Research Laboratories, West Point, PA 19486, United States.
9
Structural Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.

Abstract

Herein, we present the identification of a novel class of pyrazolopyrimidine phosphodiesterase 10A (PDE10A) inhibitors. Beginning with a lead molecule (1) identified through a fragment-based drug discovery (FBDD) effort, lead optimization was enabled by rational design, X-ray crystallography, metabolic and off-target profiling, and fragment scaffold-hopping. We highlight the discovery of PyP-1, a potent, highly selective, and orally bioavailable pyrazolopyrimidine inhibitor of PDE10A. PyP-1 exhibits sub-nanomolar potency (PDE10A Ki=0.23nM), excellent pharmacokinetic (PK) and physicochemical properties, and a clean off-target profile. It displays dose-dependent efficacy in numerous pharmacodynamic (PD) assays that measure potential for anti-psychotic activity and cognitive improvement. PyP-1 also has a clean preclinical profile with respect to cataleptic potential in rats, prolactin secretion, and weight gain, common adverse events associated with currently marketed therapeutics. Further, PyP-1 displays in vivo preclinical target engagement as measured by PET enzyme occupancy in concert with [(11)C]MK-8193, a novel PDE10A PET tracer.

KEYWORDS:

Antipsychotic activity; Cognitive improvement; Fragment-based drug discovery; Phosphodiesterase 10A; Positron emission tomography; Pyrazolopyrimidine; Rational design; Schizophrenia

PMID:
26602277
DOI:
10.1016/j.bmcl.2015.11.013
[Indexed for MEDLINE]

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