title: Discovery and in Vivo Evaluation of Potent Dual CYP11B2 (Aldosterone Synthase) and CYP11B1 Inhibitors.
abstract: Aldosterone is a key signaling component of the renin-angiotensin-aldosterone system and as such has been shown to contribute to cardiovascular pathology such as hypertension and heart failure. Aldosterone synthase (CYP11B2) is responsible for the final three steps of aldosterone synthesis and thus is a viable therapeutic target. A series of imidazole derived inhibitors, including clinical candidate 7n, have been identified through design and structure-activity relationship studies both in vitro and in vivo. Compound 7n was also found to be a potent inhibitor of 11β-hydroxylase (CYP11B1), which is responsible for cortisol production. Inhibition of CYP11B1 is being evaluated in the clinic for potential treatment of hypercortisol diseases such as Cushing's syndrome.
authors.affiliation: Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Erik L
authors.initials: EL
authors.lastname: Meredith
authors.affiliation: Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Gary
authors.initials: G
authors.lastname: Ksander
authors.affiliation: Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Lauren G
authors.initials: LG
authors.lastname: Monovich
authors.affiliation: Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Julien P N
authors.initials: JP
authors.lastname: Papillon
authors.affiliation: Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Karl
authors.initials: K
authors.lastname: Miranda
authors.affiliation: Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Patrick
authors.initials: P
authors.lastname: Morris
authors.affiliation: Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Chang
authors.initials: C
authors.lastname: Rao
authors.affiliation: Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Robin
authors.initials: R
authors.lastname: Burgis
authors.affiliation: Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Capparelli
authors.affiliation: Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Qi-Ying
authors.initials: QY
authors.lastname: Hu
authors.affiliation: Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Alok
authors.initials: A
authors.lastname: Singh
authors.affiliation: Novartis Pharmaceuticals Corporation , East Hanover, New Jersey 07936, United States.
authors.forename: Dean F
authors.initials: DF
authors.lastname: Rigel
authors.affiliation: Novartis Pharmaceuticals Corporation , East Hanover, New Jersey 07936, United States.
authors.forename: Arco Y
authors.initials: AY
authors.lastname: Jeng
authors.affiliation: Novartis Pharmaceuticals Corporation , East Hanover, New Jersey 07936, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Beil
authors.affiliation: Novartis Pharmaceuticals Corporation , East Hanover, New Jersey 07936, United States.
authors.forename: Fumin
authors.initials: F
authors.lastname: Fu
authors.affiliation: Novartis Pharmaceuticals Corporation , East Hanover, New Jersey 07936, United States.
authors.forename: Chii-Whei
authors.initials: CW
authors.lastname: Hu
authors.affiliation: Novartis Pharmaceuticals Corporation , East Hanover, New Jersey 07936, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: LaSala
keywords: CYP11B1; CYP11B2; Cushing’s syndrome; Inhibitor; aldosterone; aldosterone synthase; cortisol; enzyme; hypertension