title: Structure-Activity Relationships, Pharmacokinetics, and in Vivo Activity of CYP11B2 and CYP11B1 Inhibitors.
abstract: CYP11B2, the aldosterone synthase, and CYP11B1, the cortisol synthase, are two highly homologous enzymes implicated in a range of cardiovascular and metabolic diseases. We have previously reported the discovery of LCI699, a dual CYP11B2 and CYP11B1 inhibitor that has provided clinical validation for the lowering of plasma aldosterone as a viable approach to modulate blood pressure in humans, as well normalization of urinary cortisol in Cushing's disease patients. We now report novel series of aldosterone synthase inhibitors with single-digit nanomolar cellular potency and excellent physicochemical properties. Structure-activity relationships and optimization of their oral bioavailability are presented. An illustration of the impact of the age of preclinical models on pharmacokinetic properties is also highlighted. Similar biochemical potency was generally observed against CYP11B2 and CYP11B1, although emerging structure-selectivity relationships were noted leading to more CYP11B1-selective analogs.
authors.affiliation: †Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Julien P N
authors.initials: JP
authors.lastname: Papillon
authors.affiliation: †Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Adams
authors.affiliation: †Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Qi-Ying
authors.initials: QY
authors.lastname: Hu
authors.affiliation: †Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Changgang
authors.initials: C
authors.lastname: Lou
authors.affiliation: †Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Alok K
authors.initials: AK
authors.lastname: Singh
authors.affiliation: †Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Chun
authors.initials: C
authors.lastname: Zhang
authors.affiliation: †Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Jose
authors.initials: J
authors.lastname: Carvalho
authors.affiliation: †Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Srinivan
authors.initials: S
authors.lastname: Rajan
authors.affiliation: †Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Adam
authors.initials: A
authors.lastname: Amaral
authors.affiliation: ‡Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey 07936, United States.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Beil
authors.affiliation: ‡Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey 07936, United States.
authors.forename: Fumin
authors.initials: F
authors.lastname: Fu
authors.affiliation: †Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Eric
authors.initials: E
authors.lastname: Gangl
authors.affiliation: ‡Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey 07936, United States.
authors.forename: Chii-Whei
authors.initials: CW
authors.lastname: Hu
authors.affiliation: ‡Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey 07936, United States.
authors.forename: Arco Y
authors.initials: AY
authors.lastname: Jeng
authors.affiliation: ‡Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey 07936, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: LaSala
authors.affiliation: †Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Guiqing
authors.initials: G
authors.lastname: Liang
authors.affiliation: †Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Logman
authors.affiliation: †Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Wieslawa M
authors.initials: WM
authors.lastname: Maniara
authors.affiliation: ‡Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey 07936, United States.
authors.forename: Dean F
authors.initials: DF
authors.lastname: Rigel
authors.affiliation: †Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Sherri A
authors.initials: SA
authors.lastname: Smith
authors.affiliation: †Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Gary M
authors.initials: GM
authors.lastname: Ksander
mesh_terms: D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D003345:Corticosterone / Q000494:pharmacology; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D000450:Aldosterone; C553306:Osilodrostat; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase; D003345:Corticosterone