Conformational Restriction Approach to β-Secretase (BACE1) Inhibitors: Effect of a Cyclopropane Ring To Induce an Alternative Binding Mode

Abstract

Improvement of a drug's binding activity using the conformational restriction approach with sp³ hybridized carbon is becoming a key strategy in drug discovery. We applied this approach to BACE1 inhibitors and designed four stereoisomeric cyclopropane compounds in which the ethylene linker of a known amidine-type inhibitor 2 was replaced with chiral cyclopropane rings. The synthesis and biologic evaluation of these compounds revealed that the cis-(1S,2R) isomer 6 exhibited the most potent BACE1 inhibitory activity among them. X-ray structure analysis of the complex of 6 and BACE1 revealed that its unique binding mode is due to the apparent CH-π interaction between the rigid cyclopropane ring and the Tyr71 side chain. A derivatization study using 6 as a lead molecule led to the development of highly potent inhibitors in which the structure-activity relationship as well as the binding mode of the compounds clearly differ from those of known amidine-type inhibitors.

Cyclic acyl guanidines bearing carbamate moieties allow potent and dirigible cholinesterase inhibition of either acetyl- or butyrylcholinesterase

“…17,41,42 Interestingly, the two isomeric sets of carbamates (14-17 and 29-33) (Scheme 1A and B) show different biological profiles. N-1 Methyl substituted compounds (14)(15)(16)(17) show moderate inhibitory activities at both enzymes ranging from one to two digit micromolar activities without significant selectivity. The IC 50 (Table 1).…”

“…1). 15, 16 We had previously synthesized a series of novel tri-and tetracyclic N-bridgehead ChE inhibiting structures based on a quinazolinone moiety. 18 In 2012, we modified one lead structure by introducing a phenolic hydroxyl group in the para position to the tertiary anilinic amine, and in the meta position to the basic Nbridgehead atom (compound 5, Fig.…”

Conformational Restriction: An Effective Tactic in ‘Follow-On’-Based Drug Discovery

“…To further improve the potency of BACE1 inhibitors, structure-based evolution combined with conformational constraint strategy of these lead compounds 3, 5, 7, 9 and 11 was performed to facilitate access to the prime side of the BACE1 active site, which provided the discovery of the corresponding conformationally restricted analogues (such as 3-hydroxypyrrolidine 4 [16], imidazo[1,2-a]pyridine 6 [17], pyrrolidine 8 [18], bicyclic iminopyrimidinone 10 [19] and chiral cyclopropanes 12a-c [20,21]; Figure 1). …”

Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes. Update 2014

“…For medicinal chemistry, see [167][168][169][170][171][172] Shionogi (Osaka, in collaboration with Janssen Pharmaceuticals, Titusville, NJ, Fig. 6) is investigating conformationally restricted BACE inhibitors [173,174]. In March 2013 the drug program was listed as being in Phase I in Europe (Thomson Reuters Pharma, update of June 6, 2014).…”