This letter describes the chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0467154 (5). This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0467154, and details all of the challenges faced in allosteric modulator programs (steep SAR, species differences in PAM pharmacology and subtle structural changes affecting CNS penetration).
Pharmacology, Toxicology and Pharmaceutical Science
3
14%
Agricultural and Biological Sciences
3
14%
Chemistry
3
14%
Nursing and Health Professions
2
10%
Neuroscience
2
10%
Other
1
5%
Unknown
7
33%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 14 December 2016.
All research outputs
#17,285,036
of 25,373,627 outputs
Outputs from Bioorganic & Medicinal Chemistry Letters
#12,193
of 13,779 outputs
Outputs of similar age
#261,283
of 415,967 outputs
Outputs of similar age from Bioorganic & Medicinal Chemistry Letters
#58
of 89 outputs
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