title: Selectivity of BI 689648, a Novel, Highly Selective Aldosterone Synthase Inhibitor: Comparison with FAD286 and LCI699 in Nonhuman Primates.
abstract: The mineralocorticoid aldosterone is an important regulator of blood pressure, volume, and electrolyte balance. However, excess aldosterone can be deleterious as a driver of vascular remodeling and tissue fibrosis associated with cardiometabolic diseases. Aldosterone synthase (AS) inhibitors (ASI) attenuate the production of aldosterone directly and have been proposed as an alternative to mineralocorticoid receptor antagonists for blocking the pathologic effects of excess aldosterone. Discovery of selective ASIs has been challenging because of the high sequence identity (93%) AS shares with cortisol synthase (CS), and the low identity of rodent AS compared with human (63%). Using cynomolgus (cyno) monkey-based models, we identified BI 689648 [6-(5-methoxymethyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide], a novel, highly selective ASI that exhibits an in vitro IC50 of 2 nM against AS and 300 nm against CS (150-fold selectivity) compared with the recently described ASIs FAD286 [4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile] (3 nM AS; 90 nM CS; 40-fold) and LCI699 (4-[(5R)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl]-3-fluorobenzonitrile) (10 nM AS; 80 nM CS; 8-fold). After oral administration in cyno monkeys, BI 689648 (5 mg/kg) exhibits a peak plasma concentration of ∼500 nM. For in vivo profiling we used an adrenocorticotropin-challenge model in which BI 689648 was >20-fold more selective compared with FAD286 and LCI699. Because both FAD286 and LCI699 failed to provide adequate selectivity for CS when tested in patients, the desire for more selective molecules to test the ASI hypothesis remains high. Therefore, highly selective aldosterone synthase inhibitors such as BI 689648 represent an important step forward toward developing ASIs with greater potential for clinical success in cardiometabolic diseases.
authors.affiliation: CardioMetabolic Diseases Research (S.M.W., J-H. P., J.R.R., G.A.R., N.F.B.), and Medicinal Chemistry (M.A.C., K.G.B., D.C., X.G., N.M.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut steven.weldon@boehringer-ingelheim.com.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Weldon
authors.affiliation: CardioMetabolic Diseases Research (S.M.W., J-H. P., J.R.R., G.A.R., N.F.B.), and Medicinal Chemistry (M.A.C., K.G.B., D.C., X.G., N.M.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cerny
authors.affiliation: CardioMetabolic Diseases Research (S.M.W., J-H. P., J.R.R., G.A.R., N.F.B.), and Medicinal Chemistry (M.A.C., K.G.B., D.C., X.G., N.M.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.
authors.forename: Kristina
authors.initials: K
authors.lastname: Gueneva-Boucheva
authors.affiliation: CardioMetabolic Diseases Research (S.M.W., J-H. P., J.R.R., G.A.R., N.F.B.), and Medicinal Chemistry (M.A.C., K.G.B., D.C., X.G., N.M.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.
authors.forename: Derek
authors.initials: D
authors.lastname: Cogan
authors.affiliation: CardioMetabolic Diseases Research (S.M.W., J-H. P., J.R.R., G.A.R., N.F.B.), and Medicinal Chemistry (M.A.C., K.G.B., D.C., X.G., N.M.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.
authors.forename: Xin
authors.initials: X
authors.lastname: Guo
authors.affiliation: CardioMetabolic Diseases Research (S.M.W., J-H. P., J.R.R., G.A.R., N.F.B.), and Medicinal Chemistry (M.A.C., K.G.B., D.C., X.G., N.M.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.
authors.forename: Neil
authors.initials: N
authors.lastname: Moss
authors.affiliation: CardioMetabolic Diseases Research (S.M.W., J-H. P., J.R.R., G.A.R., N.F.B.), and Medicinal Chemistry (M.A.C., K.G.B., D.C., X.G., N.M.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.
authors.forename: Jean-Hugues
authors.initials: JH
authors.lastname: Parmentier
authors.affiliation: CardioMetabolic Diseases Research (S.M.W., J-H. P., J.R.R., G.A.R., N.F.B.), and Medicinal Chemistry (M.A.C., K.G.B., D.C., X.G., N.M.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Richman
authors.affiliation: CardioMetabolic Diseases Research (S.M.W., J-H. P., J.R.R., G.A.R., N.F.B.), and Medicinal Chemistry (M.A.C., K.G.B., D.C., X.G., N.M.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Reinhart
authors.affiliation: CardioMetabolic Diseases Research (S.M.W., J-H. P., J.R.R., G.A.R., N.F.B.), and Medicinal Chemistry (M.A.C., K.G.B., D.C., X.G., N.M.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Brown
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D017316:Fadrozole / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D009287:Naphthyridines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D013379:Substrate Specificity
chemical_list: C000619417:BI 689648; D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; D009287:Naphthyridines; D011725:Pyridines; C553306:Osilodrostat; D000324:Adrenocorticotropic Hormone; D019405:Cytochrome P-450 CYP11B2; D017316:Fadrozole