A Series of Substituted Bis-Aminotriazines Are Activators of the Natriuretic Peptide Receptor C

Figures

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  Figure 1. Structures of NPR-C active peptides and lead compound 1; active CNP peptide are displayed in red, and brackets denote disulfide bonds.

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  Figure 2. NPRC antagonist M372049, active against NPR-C.

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  Figure 3. Small molecule NPR-A and NPR-C agonists.

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  Scheme 1. Synthesis of 1,4-Cyclohexane Disubstituted Bis-Triazine and Monomeric Chlorotriazine Derivatives

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  Scheme 2. Synthesis of l-Valine Triazine Derivatives

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  Scheme 3. Synthesis of Amino Acid-Substituted Triazines

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  Figure 4. Reversal of agonist-induced vasorelaxation upon treatment with NPR-C inhibitors in rat aorta and small mesenteric artery. The selective NPR-C peptide agonist cANF4–23 causes vasorelaxation that is blocked by M372049 and osteocrin in (A) rat aorta and (B) small mesenteric artery. (C) In rat small mesenteric artery small-molecule agonist 1 causes vasorelaxation that is partially blocked by M372049 and osteocrin.

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  Figure 5. Evaluation of NPR-C agonism in HeLa cells by a cAMP assay. (A) cANF4–23 (100 nM) inhibits cAMP formation and is reversed by M372049 (10 μM) and osteocrin (100 nM); (B) M372049 and osteocrin do not affect basal forskolin-induced cAMP production. Small-molecule agonists 1 (C), 17 (D), 26 (E), and 41 (F) (100 μM) inhibit cAMP formation by 37.67, 31.43, 20.65, and 9.16%, respectively, and is reversed by M372049 and osteocrin. Data points shown in the figures represent independent biological replicates.

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  Figure 6. Human NPR-A and NPR-B agonism evaluation in HeLa cells. (A) ANP (1 μM) and CNP (1 μM) induce cGMP formation. (B) Selected compounds (10 μM) do not modify cGMP production. Data points shown in the figures represent independent biological replicates.