Discovery and SAR of a novel series of Natriuretic Peptide Receptor-A (NPR-A) agonists

Novel enhancers of guanylyl cyclase-A activity via allosteric modulation

“…Through this process, only one compound was identified as a hit. Small molecular GC-A agonists have been described previously [6][7][8] , but to our knowledge, identification of allosteric enhancers of GC-A has not been described. Our low hit rate and the fact that only a few small compounds are known to activate GC-A could be due to the structure and large interface of the orthosteric binding site.…”

“…The level of NPR-C agonism was assessed by quantifying the inhibition of forskolin-induced cyclic adenosine-3',5'-monophosphate (cAMP) production in HeLa cells. Cells were grown to around 80% confluency in 12-well plates and compounds (30 µM) or the specific NPR-C agonist cANF [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] (100 nM) were added and left to equilibrate with the cells for 10 min before the addition of forskolin (10 µM).…”

“…Natriuretic peptides (NPs) and their receptors are central regulators of cardiovascular and renal homeostasis, and enhancement of the natriuretic peptide system has become an attractive therapeutic target. Endogenous and several designer natriuretic peptides have been tested in the treatment of conditions such as heart failure [1][2][3] and hypertension 4,5 , but the development of small molecular compounds has been challenging, and only a few have been developed to target this system [6][7][8] .…”

“…Although the NP system is a validated therapeutic target, valsartan/sacubitril is currently the only small molecular compound on the market that modulates the NP system. This indicates that activation of GC-A with small molecules is challenging, and to our knowledge, only Iwaki et al have successfully developed GC-A agonists that mimic ANP and BNP [6][7][8] . Small molecular compounds like these have, in contrast to peptides, the potential of oral administration and longer half-life.…”

A New Synthesis of Gefitinib

“…Furthermore, several groups have recently demonstrated the feasibility of nucleophilic aromatic substitutions on similar quinazoline substrates under simple acidic conditions. [16][17][18] Accordingly, the dichloroquinazoline 1 was treated with 3-chloro-4-fluoroaniline in 20.4 equivalents of acetic acid at 55 °C for two hours to yield the coupling product 2 after extraction with EtOAc and filtration (Scheme 4). Under these conditions, we were able to isolate the desired 4-aminated product 2 exclusively in 65% yield on a multigram scale.…”