Abstract P233: Inhibition Of Aldosterone Synthesis In Non-human Primates By PB6440, The Novel Highly Selective And Potent CYP11B2 Inhibitor
| Autor: | Bertram Pitt, John S. Lee, Sparks Steven, Karen Morris, J. David Becherer, Robert Shotzinger, William J. Hoekstra, Deepak L. Bhatt |
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| Rok vydání: | 2020 |
| Předmět: | |
| Zdroj: | Hypertension. 76 |
| ISSN: | 1524-4563 0194-911X |
| Popis: | Aldosterone is an important mineralocorticoid responsible for fluid and electrolyte homeostasis produced by aldosterone synthase (CYP11B2). An aldosterone synthase inhibitor (ASI) may be a therapeutic option for primary aldosteronism-related conditions such as resistant hypertension. An ASI with sufficient selectivity for CYP11B2 versus the similar cortisol-producing enzyme CYP11B1 has remained elusive. PB6440 is a novel ASI that is potent and highly selective for CYP11B2. In vitro studies demonstrated 200-300-fold selectivity of PB6440 for human CYP11B2 compared to human CYP11B1. In single and multiple dose cynomolgus monkey studies of orally administered PB6440, dose-and concentration-dependent reduction of plasma aldosterone after ACTH challenge was observed with >90% reduction at higher doses. Consistent with its high selectivity, PB6440 had little effect on the CYP11B1 cortisol pathway. Plasma levels of cortisol, 11-deoxycortisol, and deoxycorticosterone, remained unchanged even at high doses of PB6440. Systolic and diastolic blood pressure was reduced in a dose-dependent manner. Circulating half-life of PB6440 was approximately 17 hours with high oral bioavailability. In summary, PB6440 is a highly selective ASI that demonstrated sustained aldosterone suppression for 14 days with no effect on the CYP11B1 pathway in non-human primates. In single and multiple dose studies, PB6440 appeared well tolerated, demonstrating good oral bioavailability, and a PK profile supportive of once daily dosing. These results suggest that PB6440 may be useful in humans as a novel therapeutic for treating hypertension or other conditions caused by excess aldosterone. |
| Databáze: | OpenAIRE |
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