Discovery of substituted 3H-pyrido[2,3-d]pyrimidin-4-ones as potent, biased, and orally bioavailable sst2 agonist

Bioorg Med Chem Lett. 2020 Nov 1;30(21):127496. doi: 10.1016/j.bmcl.2020.127496. Epub 2020 Aug 14.

Abstract

The discovery of a novel 3H-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[(2S)-pyrrolidin-2-ylmethyl]amino}methyl)-3H,4H-pyrido[2,3-d]pyrimidin-4-one (36) also suppresses GH secretion in GHRH-challenged rats in a dose-dependent manner.

Keywords: 3H-pyrido[2,3-d]pyrimidin-4-one; Acromegaly; Growth hormone (GH); Somatostatin; sst2 agonist.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Cyclic AMP / antagonists & inhibitors
  • Cyclic AMP / biosynthesis
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Male
  • Molecular Structure
  • Pyrimidinones / administration & dosage
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Interleukin-1 / agonists*
  • Structure-Activity Relationship

Substances

  • Pyrimidinones
  • Receptors, Interleukin-1
  • ST2 protein, rat
  • Cyclic AMP