In Vivo Active Aldosterone Synthase Inhibitors with Improved Selectivity: Lead Optimization Providing a Series of Pyridine Substituted 3,4-Dihydro-1H-quinolin-2-one Derivatives

Abstract

Pyridine substituted naphthalenes (e.g., I-III) constitute a class of potent inhibitors of aldosterone synthase (CYP11B2). To overcome the unwanted inhibition of the hepatic enzyme CYP1A2, we aimed at reducing the number of aromatic carbons of these molecules because aromaticity has previously been identified to correlate positively with CYP1A2 inhibition. As hypothesized, inhibitors with a tetrahydronaphthalene type molecular scaffold (1-11) exhibit a decreased CYP1A2 inhibition. However, tetralone 9 turned out to be cytotoxic to the human cell line U-937 at higher concentrations. Consequent structural optimization culminated in the discovery of heteroaryl substituted 3,4-dihydro-1H-quinolin-2-ones (12-26), with 12, a bioisostere of 9, being nontoxic up to 200 microM. The investigated molecules are highly selective toward both CYP1A2 and a wide range of other cytochrome P450 enzymes and show a good pharmacokinetic profile in vivo (e.g., 12 with a peroral bioavailability of 71%). Furthermore, isoquinoline derivative 21 proved to significantly reduce plasma aldosterone levels of ACTH stimulated rats.

Heteroatom insertion into 3,4-dihydro-1H-quinolin-2-ones leads to potent and selective inhibitors of human and rat aldosterone synthase

“…naphthalenes, [30] dihydronaphthalenes [31] and dihydroquinolinones. [34] In this study, all 4-isoquinoline substituted compounds also show stronger hCYP11B2 inhibitory activity than the parent pyridine compounds. Thus, it can be concluded that substitution of the pyridine by isoquinoline as heme-complexing group leads to a considerable improvement in hCYP11B2 inhibition without affecting selectivity toward hCYP11B1.…”

“…[34] Further modifications in this compound class were performed in this study in order to find new compounds suitable for in vivo tests in the rat.…”

“…[26] Subsequent optimization resulted in several classes of nonsteroidal highly potent hCYP11B2 inhibitors, i.e. imidazolyl-and pyridylmethylenetetrahydronaphthalenes and -indanes, [27,28] heterocycle substituted naphthalenes, dihydronaphthalenes, [29][30][31][32] pyridinyl substituted aliphatic cycles, [33] dihydroquinolinones, [34] indolines, [35] tetrahydropyrroloquinolinone, [36,37] and phenylsulfinyl naphthalenol. [38] Recently, several compound classes derived from the anaesthetic R-etomidate or the CYP19 inhibitor Fadrozole (Chart 1) were described as inhibitors of hCYP11B2.…”

“…This strategy aimed to minimize the inhibition of hepatic CYP enzymes, especially CYP1A2. [34] Heterocycle substituted 3,4-dihydro-1H-quinolinones exert a strong influence on the target enzyme (IC 50 = 0.1-64 nM) and excellent selectivities versus the highly homologous (homology > 93 %) [46] hCYP11B1 (sf = 44-440) and versus other CYP enzymes. [34] However, these compounds showed little inhibition against rat CYP11B2 and thus made it difficult to perform in vivo studies in this well established animal model.…”

“…The aim is to increase inhibition of rCYP11B2 while maintaining the potency and selectivity toward human enzymes. First trials to test this approach for the class of dihydroquinolinone type CYP11B2 inhibitors were performed by us recently [34] By introduction of sulfur instead of the methylene bridge in position 4 (compound II), inhibitory potency for hCYP11B2 was enhanced by a factor of two, thus suggesting that the introduced heteroatom is able to undergo interactions with the binding site of the enzyme. To avoid potential metabolic oxidation of the sulfur bridge, we decided to focus on oxygen and nitrogen as heteroatoms in this study.…”