Potent and Selective ET-A Antagonists. 2. Discovery and Evaluation of Potent and Water Soluble N-(6-(2-(Aryloxy)ethoxy)-4-pyrimidinyl)sulfonamide Derivatives

Abstract

In the preceding article,(1) we outlined the discovery and structure-activity relationship of a potent and selective ET(A) receptor antagonist 1 and its related compounds. Metabolites of 1 having potent selective ET(A) receptor antagonist activity were identified. This study suggested the metabolic pathways of 1 were considerably affected by species. Consequently, structural modification of 1 intended to improve the complexity of the metabolic pathway, and water solubility was performed. The subsequent introduction of a hydroxyl group into the tert-butyl moiety of 1 led to the discovery of our new clinical candidate, 6b, which showed a higher water solubility, a uniform metabolic pathway among species, and very high affinity and selectivity for the human ET(A) receptor (K(i) for ET(A) receptor: 0.015 +/- 0.004 nM; for ET(B) receptor: 41 +/- 21 nM).

The Discovery of N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N′-propylsulfamide (Macitentan), an Orally Active, Potent Dual Endothelin Receptor Antagonist

“…Inspired by the structure of Tanabe’s clinical development compound N -(6-(2-((5-bromopyrimidin-2-yl)­oxy)­ethoxy)-5-( p -tolyl)­pyrimidin-4-yl)-4-(1-hydroxy-2-methylpropan-2-yl)­benzenesulfonamide (T-0201, 2 ) (Figure ), we were curious to learn how the introduction of a pyrimidine to the ethylene glycol moiety of compound 1 would influence its affinity for the two endothelin receptors. In a first study illustrated by the compounds listed in Table , we observed that such an additional pyrimidine ring improves the affinity for ET A and ET B significantly.…”

“…This encouraged us to further evaluate the sulfamide series with scaffolds lacking a substituent in position 2 of the core pyrimidine. We therefore prepared a number of 2-unsubstituted pyrimidine derivatives incorporating a selection of 5-substituents that were known to lead to potent ET receptor antagonists. − Some examples are compiled in Table . As shown with compounds 52 and 53 , a 3-methoxyphenoxy rather than a 2-methoxyphenoxy substituent led to an increase in potency on ET A but left the affinity for ET B unchanged.…”