Winneroski, LL; Erickson, JA; Green, SJ; Lopez, JE; Stout, SL; Porter, WJ; Timm, DE; Audia, JE; Barberis, M; Beck, JP; Boggs, LN; Borders, AR; Boyer, RD; Brier, RA; Hembre, EJ; Hendle, J; Garcia-Losada, P; Minguez, JM; Mathes, BM; May, PC; Monk, SA; Rankovic, Z; Shi, Y; Watson, BM; Yang, Z; Mergott, DJ
Inhibition of BACE1 has become an important strategy in the quest for disease modifying agents to slow the progression of Alzheimer's disease. We previously reported the fragment-based discovery of LY2811376, the first BACE1 inhibitor reported to demonstrate robust reduction of human CSF Aβ in a Phase I clinical trial. We also reported on the discovery of LY2886721, a potent BACE1 inhibitor that reached phase 2 clinical trials. Herein we describe the preparation and structure activity relationships (SAR) of a series of BACE1 inhibitors utilizing trans-cyclopropyl moieties as conformational constraints. The design, details of the stereochemically complex organic synthesis, and biological activity of these BACE1 inhibitors is described. © 2019 Elsevier Ltd
Alzheimer's disease; BACE1 inhibitor; Conformational constraint; Cyclopropyl; Structure-based drug design; 1 chloro 3 (triphenyl lambda phosphaneylidene)propan 2 one; 2 [(4ar,7ar) 2 benzamido 6 (pyrimidin 2 yl) 4a,5,6,7 tetrahydropyrrolo[3,4 d][1,3]thiazin 7a(4h) yl]cyclopropane 1 carboxylic acid; 7a [2 (2 methylcyclopropyl) methoxy propan 2 yl cyclopropyl] 6 (pyrimidin 2 yl) 4,4a,5,6,7,7a hexahydropyrrolo[3,4 d][1,3]thiazin 2 amine; enzyme inhibitor; ethyl 2 [n allyl n (tert butoxycarbonyl)glycyl]cyclopropane 1 carboxylate; ethyl [(4ar,7ar) 2 benzamido 4a,5,6,7 tetrahydro 4h pyrrolo[ 3,4 d][1,3]thiazin 7a yl]cyclopropanecarboxylate di hydrochloride; ethyl [(4ar,7ar) 2 benzamido 6 (pyrimidin 2 yl) 4a,5,6,7 tetrahydropyrrolo[3,4 d][1,3]thiazin 7a(4h)yl]cyclopropane 1 carboxylate; ly 2811376; n [(4ar,7ar) 7a 2 (2 hydroxypropan 2 yl) cyclopropyl 6 (pyrimidin 2 yl) 4,4a,5,6,7,7a hexahydropyrrolo[3,4 d] [1,3]thiazin 2 yl]benzamide; n [(4ar,7ar) 7a [2 (2 methylcyclopropyl) methoxy propan 2 yl cyclopropyl] 6 (pyrimidin 2 yl) 4,4a,5,6,7,7a hexahydropyrrolo[3,4 d][1,3]thiazin 2 yl]benzamide; tert butyl (3ar,6ar) 2 benzamido 7a 2 (ethoxycarbonyl)cyclopropyl 4a,5,7,7a tetrahydropyrrolo[3,4 d][1,3]thiazine 6 (4h) carboxylate; tert butyl (3ar,6ar) 6a 2 (ethoxycarbonyl) cyclopropyl 1 (4 methoxybenzyl)tetrahydro 1h pyrrolo[3,4 c]isoxazole 5(3h)carboxylate; tert butyl 3 (benzoylcarbamothioylamino) 3 [trans 2 ethoxycarbonylcyclopropyl] 4 (hydroxymethyl)pyrrolidine 1 carboxylate; tert butyl 3 amino 3 2 (ethoxycarbonyl)cyclopropyl 4(hydroxymethyl)pyrrolidine 1 carboxylate; tert butyl allyl(2 oxobut 3 en 1 yl)carbamate; tert butyl [2 oxo 3(triphenyl lambda phosphaneylidene)propyl]carbamate; unclassified drug; aspartic proteinase; BACE1 protein, human; cyclopropane derivative; ligand; proteinase inhibitor; secretase; animal cell; Article; biological activity; conformation; drug design; drug potency; drug screening; drug structure; drug synthesis; human; human cell; in vitro study; mouse; nonhuman; rat; stereochemistry; structure activity relation; Alzheimer disease; chemistry; conformation; dose response; metabolism; molecular model; synthesis; X ray crystallography; Alzheimer Disease; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Crystallography, X-Ray; Cyclopropanes; Dose-Response Relationship, Drug; Humans; Ligands; Models, Molecular; Molecular Conformation; Protease Inhibitors; Structure-Activity Relationship