Fine-Tuning the Selectivity of Aldosterone Synthase Inhibitors: Structure−Activity and Structure−Selectivity Insights from Studies of Heteroaryl Substituted 1,2,5,6-Tetrahydropyrrolo[3,2,1-ij]quinolin-4-one Derivatives

Abstract

Pyridine substituted 3,4-dihydro-1H-quinolin-2-ones (e.g., 1-3) constitute a class of highly potent and selective inhibitors of aldosterone synthase (CYP11B2), a promising target for the treatment of hyperaldosteronism, congestive heart failure, and myocardial fibrosis. Among these, ethyl-substituted 3 possesses high selectivity against CYP1A2. Rigidification of 3 by incorporation of the ethyl group into a 5- or 6-membered ring affords compounds with a pyrroloquinolinone or pyridoquinolinone molecular scaffold (e.g., 4 and 5). It was found that these molecules are even more potent and selective CYP11B2 inhibitors than their corresponding open-chain analogues. Moreover, pyrroloquinolinone 4 exhibits no inhibition of the six most important hepatic CYP enzymes as well as a bioavailability in the range of the marketed drug fadrozole. The SAR studies disclose that subtle changes in the heterocyclic moiety are responsible for either a strong or a weak inhibition of the highly homologous 11β-hydroxylase (CYP11B1). These results are not only important for fine-tuning the selectivity of CYP11B2 inhibitors but also for the development of selective CYP11B1 inhibitors that are of interest for the treatment of Cushing's syndrome and metabolic syndrome.

D–π–A Triarylboron Compounds with Tunable Push–Pull Character Achieved by Modification of Both the Donor and Acceptor Moieties

“…Furthermore, we note that simple adaption of the method might also be expected to expedite the synthesis of related Bpinsubstituted planarized triphenylamines [19] and 2,6-substituted anilines [20] of pharmaceutical relevance, both of which otherwise require a two-step procedure of bromination and Pd-catalyzed Miyaura borylation. Key precursors Br-Pfp and Br-Tfp, required for modifying the boryl moiety, were prepared by Ir-catalyzed C-H borylation of 2,6-dimethylbromobenzene at the 4-position in 95% yield on a multi-gram scale, and subsequent Suzuki-Miyaura cross coupling with pentafluoroiodobenzene or 3,5-bis(trifluoromethyl)iodobenzene in 79-80% yield; notably, the borylation reaction was regiospecific and was, therefore, pivotal to ensuring high isolated yields of the products.…”

Discovery of new 7-substituted-4-imidazolylmethyl coumarins and 4′-substituted-2-imidazolyl acetophenones open analogues as potent and selective inhibitors of steroid-11β-hydroxylase

“…Unfortunately, the discovery of highly selective CYP11B1 inhibitors is not a simple task because the two CYP enzymes present a very high sequence homology and, moreover, the lack of experimental 3D models prevents the use of structure-based approaches for the design of potent and selective inhibitors. Pharmacophore and 3D QSAR models have been recently developed, [18][19][20][21] but the relatively limited molecular diversity explored might preclude their sound application in the design of completely novel and selective inhibitors. Despite these objective drawbacks, careful evaluation of the structure-activity and structureselectivity relationships (SAR and SSR, respectively) allowed the discovery of potent and highly selective CYP11B2 [22][23][24][25][26] and potent but slightly selective CYP11B1 inhibitors.…”

“…Pharmacophore and 3D QSAR models have been recently developed, [18][19][20][21] but the relatively limited molecular diversity explored might preclude their sound application in the design of completely novel and selective inhibitors. Despite these objective drawbacks, careful evaluation of the structure-activity and structureselectivity relationships (SAR and SSR, respectively) allowed the discovery of potent and highly selective CYP11B2 [22][23][24][25][26] and potent but slightly selective CYP11B1 inhibitors. [7][8][9][10] Two of the best compounds discovered in recent studies (e.g., A [8] and B [14] in Chart2) displayed very good to moderately potent CYP11B1 inhibition (IC 50 = 2 and 107 nM, respectively) and moderate selectivity indices (SIB= 13.3 and 16.5, respectively; SIB= IC 50 CYP11B2/IC 50 CYP11B1) but greater than that observed for metyrapone (SIB= 4.8).…”

Cascade reaction synthesis of multisubstituted bicyclic pyridone derivatives

“…1 Among them, substituted bicyclic pyridones possess a broad range of pharmacological activities, including CB 2 agonists, 2 (the inhibitors of aldosterone synthase, 3 Amyloidb-peptide aggregation, 4 irreversible 3CP, 5 pilus formation in uropathogenic Escherichia coli, 6,7 ACE (A58365A & A58365B, Fig. 1)).…”