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An Orally Available BACE1 Inhibitor That Affords Robust CNS A? Reduction without Cardiovascular Liabilities.

ABSTRACT: BACE1 inhibition to prevent A? peptide formation is considered to be a potential route to a disease-modifying treatment for Alzheimer's disease. Previous efforts in our laboratory using a combined structure- and property-based approach have resulted in the identification of aminooxazoline xanthenes as potent BACE1 inhibitors. Herein, we report further optimization leading to the discovery of inhibitor 15 as an orally available and highly efficacious BACE1 inhibitor that robustly reduces CSF and brain A? levels in both rats and nonhuman primates. In addition, compound 15 exhibited low activity on the hERG ion channel and was well tolerated in an integrated cardiovascular safety model.

SUBMITTER: Cheng Y

PROVIDER: S-EPMC4329588 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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An Orally Available BACE1 Inhibitor That Affords Robust CNS Aβ Reduction without Cardiovascular Liabilities.

Cheng Yuan Y Brown James J Judd Ted C TC Lopez Patricia P Qian Wenyuan W Powers Timothy S TS Chen Jian Jeffrey JJ Bartberger Michael D MD Chen Kui K Dunn Robert T RT Epstein Oleg O Fremeau Robert T RT Harried Scott S Hickman Dean D Hitchcock Stephen A SA Luo Yi Y Minatti Ana Elena AE Patel Vinod F VF Vargas Hugo M HM Wahl Robert C RC Weiss Matthew M MM Wen Paul H PH White Ryan D RD Whittington Douglas A DA Zheng Xiao Mei XM Wood Stephen S

ACS medicinal chemistry letters 20141229 2

BACE1 inhibition to prevent Aβ peptide formation is considered to be a potential route to a disease-modifying treatment for Alzheimer's disease. Previous efforts in our laboratory using a combined structure- and property-based approach have resulted in the identification of aminooxazoline xanthenes as potent BACE1 inhibitors. Herein, we report further optimization leading to the discovery of inhibitor 15 as an orally available and highly efficacious BACE1 inhibitor that robustly reduces CSF and ...[more]

PMID: 25699151

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Project description:BACKGROUND AND OBJECTIVES:In the Systolic Blood Pressure Intervention Trial (SPRINT), intensive systolic BP treatment (target <120 mm Hg) was associated with fewer cardiovascular events and higher incidence of kidney function decline compared with standard treatment (target <140 mm Hg). We evaluated the association between mean arterial pressure reduction, kidney function decline, and cardiovascular events in patients without CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:We categorized patients in the intensive treatment group of the SPRINT according to mean arterial pressure reduction throughout follow-up: <20, 20 to <40, and ?40 mm Hg. We defined the primary outcome as kidney function decline (?30% reduction in eGFR to <60 ml/min per 1.73 m2 on two consecutive determinations at 3-month intervals), and we defined the secondary outcome as cardiovascular events. In a propensity score analysis, patients in each mean arterial pressure reduction category from the intensive treatment group were matched with patients from the standard treatment group to calculate the number needed to treat regarding cardiovascular events and the number needed to harm regarding kidney function decline. RESULTS:In the intensive treatment group, 1138 (34%) patients attained mean arterial pressure reduction <20 mm Hg, 1857 (56%) attained 20 to <40 mm Hg, and 309 (9%) attained ?40 mm Hg. Adjusted hazard ratios for kidney function decline were 2.10 (95% confidence interval, 1.22 to 3.59) for mean arterial pressure reduction between 20 and 40 mm Hg and 6.22 (95% confidence interval, 2.75 to 14.08) for mean arterial pressure reduction ?40 mm Hg. In propensity score analysis, mean arterial pressure reduction <20 mm Hg presented a number needed to treat of 44 and a number needed to harm of 65, reduction between 20 and <40 mm Hg presented a number needed to treat of 42 and a number needed to harm of 35, and reduction ?40 mm Hg presented a number needed to treat of 95 and a number needed to harm of 16. CONCLUSIONS:In the intensive treatment group of SPRINT, larger declines in mean arterial pressure were associated with higher incidence of kidney function decline. Intensive treatment seemed to be less favorable when a larger reduction in mean arterial pressure was needed to attain the BP target.

Dataset Information

An Orally Available BACE1 Inhibitor That Affords Robust CNS A? Reduction without Cardiovascular Liabilities.

Publications

An Orally Available BACE1 Inhibitor That Affords Robust CNS Aβ Reduction without Cardiovascular Liabilities.

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