title: Discovery of pyrrolidine-based β-secretase inhibitors: lead advancement through conformational design for maintenance of ligand binding efficiency.
abstract: We have developed a novel series of pyrrolidine derived BACE-1 inhibitors. The potency of the weak initial lead structure was enhanced using library-based SAR methods. The series was then further advanced by rational design while maintaining a minimal ligand binding efficiency threshold. Ultimately, the co-crystal structure was obtained revealing that these inhibitors interacted with the enzyme in a unique fashion. In all, the potency of the series was enhanced by 4 orders of magnitude from the HTS lead with concomitant increases in physical properties needed for series advancement. The progression of these developments in a systematic fashion is described.
authors: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., PO Box 4, West Point, PA 19486, USA. shawn_stachel@merck.com
authors: Shawn J
authors: SJ
authors: Stachel
authors: Thomas G
authors: TG
authors: Steele
authors: Alessia
authors: A
authors: Petrocchi
authors: Sharie J
authors: SJ
authors: Haugabook
authors: Georgia
authors: G
authors: McGaughey
authors: M
authors: M
authors: Katharine Holloway
authors: Timothy
authors: T
authors: Allison
authors: Sanjeev
authors: S
authors: Munshi
authors: Paul
authors: P
authors: Zuck
authors: Dennis
authors: D
authors: Colussi
authors: Katherine
authors: K
authors: Tugasheva
authors: Abigail
authors: A
authors: Wolfe
authors: Samuel L
authors: SL
authors: Graham
authors: Joseph P
authors: JP
authors: Vacca
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003460:Crystallization; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008024:Ligands; D008956:Models, Chemical; D011485:Protein Binding; D011759:Pyrrolidines / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D011759:Pyrrolidines; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human