title: Design and synthesis of potent, orally efficacious hydroxyethylamine derived β-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors.
abstract: We have previously shown that hydroxyethylamines can be potent inhibitors of the BACE1 enzyme and that the generation of BACE1 inhibitors with CYP 3A4 inhibitory activities in this scaffold affords compounds (e.g., 1) with sufficient bioavailability and pharmacokinetic profiles to reduce central amyloid-β peptide (Aβ) levels in wild-type rats following oral dosing. In this article, we describe further modifications of the P1-phenyl ring of the hydroxyethylamine series to afford potent, dual BACE1/CYP 3A4 inhibitors which demonstrate improved penetration into the CNS. Several of these compounds caused robust reduction of Aβ levels in rat CSF and brain following oral dosing, and compound 37 exhibited an improved cardiovascular safety profile relative to 1.
authors.affiliation: Chemical Research and Discovery, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States. tdineen@amgen.com
authors.forename: Thomas A
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authors.lastname: Dineen
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authors.lastname: Monenschein
authors.forename: Thomas T
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authors.forename: Lewis D
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authors.forename: E Allen
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authors.lastname: Sickmier
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authors.forename: Qiufen
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authors.lastname: Xue
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mesh_terms: D000284:Administration, Oral; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D018360:Crystallography, X-Ray; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004285:Dogs; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D010446:Peptide Fragments / Q000134:cerebrospinal fluid / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D001798:Blood Proteins; D065607:Cytochrome P-450 Enzyme Inhibitors; D010446:Peptide Fragments; D013141:Spiro Compounds; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509281:Bace1 protein, rat