Structure−Activity Relationships of a Novel Class of Endothelin-A Receptor Antagonists and Discovery of Potent and Selective Receptor Antagonist, 2-(Benzo[1,3]dioxol-5-yl)-6-isopropyloxy-4-(4-methoxyphenyl)-2H-chromene-3- carboxylic Acid (S-1255). 1. Study on Structure−Activity Relationships and Basic Structure Crucial for ET_A Antagonism

Abstract

A novel series of endothelin-A (ET(A)) selective receptor antagonists having a 2H-chromene skeleton are described. A lead compound, 2-(benzo[1,3]dioxol-5-yl)-2H-chromene-3-carboxylic acid (3), was found by modifications of our own angiotensin II antagonist. A structure-activity relationship (SAR) study of 3 reveals that the structural requirements essential for potent and selective ET(A) receptor binding affinity are the m,p-methylenedioxyphenyl, carboxyl, and isopropoxy groups at the 2-, 3-, and 6-positions, respectively, on the (R)-2H-chromene skeleton. The substituent at the 4-position is also important for improving the activity, and various hydrophobic functional groups of 6-9 A such as liner, branched, and cyclic aliphatic groups, unsubstituted and substituted aryl groups, and even halogen atoms were acceptable. These results suggest that (R)-2-(benzo[1,3]dioxol-5-yl)-6-isopropoxy-2H-chromene-3-carboxylic acid, formula 108, is the crucial basic structure to be recognized by the ET(A) receptor. The most potent compound is (R)-48 (S-1255), which binds to the ET(A) receptor with an IC(50) value of 0.19 nM and is 630-fold selective for the ET(A) receptor than for the ET(B) receptor. This compound has 55% oral bioavailability in rats. On the basis of the SAR, the roles of each substituent in the receptor binding are discussed.

Synthesis of 3-substituted 2-trifluoro(trichloro)methyl-2H-chromenes by reaction of salicylaldehydes with activated trihalomethyl alkenes

“…Although these compounds are not found in nature, their derivatives are reported to be useful from industrial and medical points of view [40,41]. These facts and our continuing interest in the chemistry of trifluoromethyl analogues of natural chromans and chromenes [19,20,25] led us to investigate the synthesis of the hitherto unknown 2-CX 3 -3-R-2H-chromenes (X = F, Cl; R = COPh, NO 2 ).…”

“…Next, we investigated the reaction of salicylaldehydes 1 with (E)-3,3,3-trifluoro-and 3,3,3-trichloro-1-nitroprop-1-enes (2b,c), for this, it was anticipated, would give a range of new trihalomethylated 3-nitro-2H-chromenes as precursors to a variety of medicinally important chroman derivatives [40,41]. It turned out that unlike alkene 2a, the reaction of trihaloethylidene nitromethanes 2b,c with salicylaldehydes 1 is much faster, reaching completion within 10 min to 2 h. Moreover, under the conditions used, additional step to affect dehydration of the corresponding chromanols 3 was not necessary since the reaction proceeded smoothly to give 2-trifluoromethyl-and 2-trichloromethyl-3-nitro-2H-chromenes 4c-f directly in 76-99% yields (Scheme 2).…”

Atropoisomerismo: o efeito da quiralidade axial em substâncias bioativas

“…Neste contexto, estudando a correlação estrutura-atividade de uma classe de ligantes de receptores de endotelina A (ET A ), Ishizuka et al 59 identificaram que o derivado cromênico 56 apresentou propriedades antagonistas potentes e seletivas (Figura 23). Posteriormente, novos estudos de relação estrutura-atividade 60 demonstraram a importância do fenô-meno de atropoisomerismo do grupo R em relação ao anel B para a afinidade com o receptor ET A , uma vez que os melhores resultados indicam que a conformação bioativa deve apresentar uma relação ortogonal entre os grupos arila R/B, também chamada de efeito L. Esta observação baseou-se no fato dos compostos 59 e 60, apresentando a ligação C 3 -C 4 saturada, não apresentarem atropoisomerismo e valores de IC 50 maiores que seus respectivos análogos insaturados 56 e 58.…”

Insights into ETA subtype selectivity of benzodiazepine endothelin receptor antagonists by 3D-QSAR approaches

“…Recently, a number of selective as well as nonselective endothelin receptor antagonists are being actively developed as new therapeutic agents [5][6][7][8]. Extensive preclinical and clinical studies, mainly with ET A receptor antagonists, have shown excellent therapeutic benefits in disease such as pulmonary hypertension [9], heart failure [10], atherosclerosis [11], systemic hypertension [12], chronic renal failure [13] and solid tumors [14].…”

“…These results indicate endothelin receptor antagonists, especially those selective for the ET A receptor subtype, may constitute a novel and potentially important class of agents for the treatment of the aforementioned pathological conditions. Selective inhibition of ET A receptors may be preferential to non-selective receptor antagonism by permitting maintenance of vasodilator and clearance functions specific to ET B receptors on the endothelial cells, while preventing the vasoconstriction and cellular proliferation mediated by ET A [7].…”