Discovery of substituted 3H-pyrido[2, 3-d]pyrimidin-4-ones as potent, biased, and orally bioavailable sst2 agonist. Issue 21 (1st November 2020)

• Record Type: Journal Article
• Authors: Zhao, Jian; Chen, Zhiyong; Kusnetzow, Ana Karin; Nguyen, Julie; Rico-Bautista, Elizabeth; Tan, Hannah; Betz, Stephen F.; Struthers, R. Scott; Zhu, Yunfei
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 21(2020)
• Publication Date: 2020-11-01
• Subjects: Somatostatin -- sst2 agonist -- Acromegaly -- Growth hormone (GH) -- 3H-pyrido[2, 3-d]pyrimidin-4-one; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127496
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: The discovery of a novel 3 H -pyrido[2, 3-d]pyrimidin-4-one series as potent and biased sst2 agonists is described. This class of molecules exhibits excellent sst2 potency and selectivity against sst1, sst3, and sst5 receptors, and they are significantly more potent at inhibiting cAMP production than inducing internalization. The orally bioavailable 6-(3-chloro-5-methylphenyl)-3-(3-fluoro-5-hydroxyphenyl)-5-({methyl[(2 S )-pyrrolidin-2-ylmethyl]amino}methyl)-3 H, 4 H -pyrido[2, 3-d]pyrimidin-4-one (36) also suppresses GH secretion in GHRH-challenged rats in a dose-dependent manner.