Discovery of N‑[5-(6-Chloro-3-cyano-1-methyl‑1H‑indol-2-yl)-pyridin-3-ylmethyl]-ethanesulfonamide, a Cortisol-Sparing CYP11B2 Inhibitor that Lowers Aldosterone in Human Subjects
Human clinical studies conducted with LCI699 established aldosterone synthase (CYP11B2) inhibition as a promising novel mechanism to lower arterial blood pressure. However, LCI699’s low CYP11B1/CYP11B2 selectivity resulted in blunting of adrenocorticotropic hormone-stimulated cortisol secretion. Thi...
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| Published in | Journal of medicinal chemistry Vol. 58; no. 23; pp. 9382 - 9394 |
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| Main Authors | , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
WASHINGTON
American Chemical Society
10.12.2015
Amer Chemical Soc |
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| Abstract | Human clinical studies conducted with LCI699 established aldosterone synthase (CYP11B2) inhibition as a promising novel mechanism to lower arterial blood pressure. However, LCI699’s low CYP11B1/CYP11B2 selectivity resulted in blunting of adrenocorticotropic hormone-stimulated cortisol secretion. This property of LCI699 prompted its development in Cushing’s disease, but limited more extensive clinical studies in hypertensive populations, and provided an impetus for the search for cortisol-sparing CYP11B2 inhibitors. This paper summarizes the discovery, pharmacokinetics, and pharmacodynamic data in preclinical species and human subjects of the selective CYP11B2 inhibitor 8. |
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| AbstractList | Human clinical studies conducted with LCI699 established aldosterone synthase (CYP11B2) inhibition as a promising novel mechanism to lower arterial blood pressure. However, LCI699's low CYP11B1/CYP11B2 selectivity resulted in blunting of adrenocorticotropic hormone-stimulated cortisol secretion. This property of LCI699 prompted its development in Cushing's disease, but limited more extensive clinical studies in hypertensive populations, and provided an impetus for the search for cortisol-sparing CYP11B2 inhibitors. This paper summarizes the discovery, pharmacokinetics, and pharmacodynamic data in predinical species and human subjects of the selective CYP11B2 inhibitor 8. Human clinical studies conducted with LCI699 established aldosterone synthase (CYP11B2) inhibition as a promising novel mechanism to lower arterial blood pressure. However, LCI699's low CYP11B1/CYP11B2 selectivity resulted in blunting of adrenocorticotropic hormone-stimulated cortisol secretion. This property of LCI699 prompted its development in Cushing's disease, but limited more extensive clinical studies in hypertensive populations, and provided an impetus for the search for cortisol-sparing CYP11B2 inhibitors. This paper summarizes the discovery, pharmacokinetics, and pharmacodynamic data in preclinical species and human subjects of the selective CYP11B2 inhibitor 8. |
| Author | Russell, Kerry S Ksander, Gary M Beil, Michael E Liang, Guiqing Lou, Changgang Vest, John A Adams, Christopher M Papillon, Julien P. N Rigel, Dean F Chen, Wei Leung-Chu, Jennifer Gan, Lu Hu, Chii-Whei Jeng, Arco Y Watson, Catherine Singh, Alok K LaSala, Daniel Fu, Fumin |
| AuthorAffiliation | Drug Metabolism and Pharmacokinetics Global Discovery Chemistry Cardiovascular and Metabolism Metabolism and Pharmacokinetics Novartis Institutes for BioMedical Research Translational Medicine |
| AuthorAffiliation_xml | – name: Novartis Institutes for BioMedical Research – name: Cardiovascular and Metabolism – name: Drug Metabolism and Pharmacokinetics – name: Translational Medicine – name: Global Discovery Chemistry – name: Metabolism and Pharmacokinetics |
| Author_xml | – sequence: 1 givenname: Julien P. N surname: Papillon fullname: Papillon, Julien P. N email: julien.papillon@novartis.com – sequence: 2 givenname: Changgang surname: Lou fullname: Lou, Changgang – sequence: 3 givenname: Alok K surname: Singh fullname: Singh, Alok K – sequence: 4 givenname: Christopher M surname: Adams fullname: Adams, Christopher M – sequence: 5 givenname: Gary M surname: Ksander fullname: Ksander, Gary M – sequence: 6 givenname: Michael E surname: Beil fullname: Beil, Michael E – sequence: 7 givenname: Wei surname: Chen fullname: Chen, Wei – sequence: 8 givenname: Jennifer surname: Leung-Chu fullname: Leung-Chu, Jennifer – sequence: 9 givenname: Fumin surname: Fu fullname: Fu, Fumin – sequence: 10 givenname: Lu surname: Gan fullname: Gan, Lu – sequence: 11 givenname: Chii-Whei surname: Hu fullname: Hu, Chii-Whei – sequence: 12 givenname: Arco Y surname: Jeng fullname: Jeng, Arco Y – sequence: 13 givenname: Daniel surname: LaSala fullname: LaSala, Daniel – sequence: 14 givenname: Guiqing surname: Liang fullname: Liang, Guiqing – sequence: 15 givenname: Dean F surname: Rigel fullname: Rigel, Dean F – sequence: 16 givenname: Kerry S surname: Russell fullname: Russell, Kerry S – sequence: 17 givenname: John A surname: Vest fullname: Vest, John A – sequence: 18 givenname: Catherine surname: Watson fullname: Watson, Catherine |
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| Keywords | IN-VIVO ACTIVITY 11-BETA-HYDROXYLASE INHIBITOR POTENT SYNTHASE INHIBITION RESISTANT HYPERTENSION HEART-FAILURE SELECTIVE INHIBITORS DOUBLE-BLIND CARDIAC FIBROSIS ANGIOTENSIN |
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| SubjectTerms | Aldosterone - metabolism Animals Chemistry, Medicinal Cytochrome P-450 CYP11B2 - antagonists & inhibitors Cytochrome P-450 CYP11B2 - metabolism Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - pharmacology Halogenation Haplorhini Humans Hypertension - drug therapy Indoles - chemistry Indoles - pharmacokinetics Indoles - pharmacology Life Sciences & Biomedicine Methylation Mineralocorticoid Receptor Antagonists - chemistry Mineralocorticoid Receptor Antagonists - pharmacokinetics Mineralocorticoid Receptor Antagonists - pharmacology Pharmacology & Pharmacy Pyridines - chemistry Pyridines - pharmacokinetics Pyridines - pharmacology Rats Rats, Sprague-Dawley Science & Technology Sulfonamides - chemistry Sulfonamides - pharmacokinetics Sulfonamides - pharmacology |
| Title | Discovery of N‑[5-(6-Chloro-3-cyano-1-methyl‑1H‑indol-2-yl)-pyridin-3-ylmethyl]-ethanesulfonamide, a Cortisol-Sparing CYP11B2 Inhibitor that Lowers Aldosterone in Human Subjects |
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