ArticleBioorganic & medicinal chemistry letters2016
Discovery and optimization of a novel series of highly CNS penetrant M4 PAMs based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3-d]pyrimidine core.
Article in Bioorganic & medicinal chemistry letters, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Drug Design Targeting the Muscarinic Receptors and the Implications in Central Nervous System Disorders.Biomedicines · 2022Review
- Fine Tuning Muscarinic Acetylcholine Receptor Signaling Through Allostery and Bias.Frontiers in pharmacology · 2020Review
- SAR inspired by aldehyde oxidase (AO) metabolism: Discovery of novel, CNS penetrant tricyclic MBioorganic & medicinal chemistry letters · 2019Article
- Novel MBioorganic & medicinal chemistry letters · 2019Article
- Challenges in the development of an MBioorganic & medicinal chemistry letters · 2017Article
- Discovery of a novel 2,4-dimethylquinoline-6-carboxamide MBioorganic & medicinal chemistry letters · 2017Article
- Discovery of a novel, CNS penetrant MBioorganic & medicinal chemistry letters · 2017Article
- Challenges in the development of an MBioorganic & medicinal chemistry letters · 2017Article
- Optimization of MBioorganic & medicinal chemistry letters · 2017Article
- Discovery of VU0467485/AZ13713945: An MACS medicinal chemistry letters · 2017Article
- Challenges in the development of an MBioorganic & medicinal chemistry letters · 2017Article
- Discovery and SAR of a novel series of potent, CNS penetrant M4 PAMs based on a non-enolizable ketone core: Challenges in disposition.Bioorganic & medicinal chemistry letters · 2016Article
Corrections and comments
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Authors and funding
25 authors.
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Abstract
This Letter describes the chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3-d]pyrimidine core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent and selective, but not CNS penetrant. Potency was maintained, while CNS penetration was improved (rat brain:plasma Kp=0.74), within the original core after several rounds of optimization; however, the thieno[2,3-d]pyrimidine core was subject to extensive oxidative metabolism. Ultimately, we identified a 6-fluoroquinazoline core replacement that afforded good M4 PAM potency, muscarinic receptor subtype selectivity and CNS penetration (rat brain:plasma Kp>10). Moreover, this campaign provided fundamentally distinct M4 PAM chemotypes, greatly expanding the available structural diversity for this exciting CNS target.
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Registered trials
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