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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. [ABSTRACT FROM AUTHOR]