Design, synthesis and in vivo study of novel pyrrolidine-based 11β-HSD1 inhibitors for age-related cognitive dysfunction

Abstract

Recent findings suggest that treatment with 11β-HSD1 inhibitors provides a novel approach to deal with age-related cognitive dysfunctions, including Alzheimer's disease. In this work we report potent 11β-HSD1 inhibitors featuring unexplored pyrrolidine-based polycyclic substituents. A selected candidate administered to 12-month-old SAMP8 mice for four weeks prevented memory deficits and displayed a neuroprotective action. This is the first time that 11β-HSD1 inhibitors have been studied in this broadly-used mouse model of accelerated senescence and late-onset Alzheimer's disease.

Exploring N-acyl-4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-enes as 11β-HSD1 Inhibitors

“…Subsequently, we performed an in vivo study with 3 in the Senescence-Accelerated Mouse Prone 8 (SAMP8) model of cognitive dysfunction in order to support the neuroprotective effect of 11β-HSD1 inhibition in cognitive decline related to the aging process. We found that 3 , administered to 12-month-old SAMP8 mice for four weeks, prevented memory deficits and displayed a neuroprotective action through reduction of neuroinflammation and oxidative stress, in cognitive decline related to the aging process [ 17 ]. These promising results with an early lead without optimal selectivity and DMPK (drug metabolism and pharmacokinetics) properties led us to investigate additional potent 11β-HSD1 inhibitors that maintained the optimized polycycle of compound 2 while modifying the right-hand side (RHS) substituent of the structure.…”

“…A series of different substituents were integrated into the RHS moiety, while the amido linker was retained to enable the key hydrogen bonds in the binding site [ 17 ]. A diversity of substituents was generated including aromatic, heteroaromatic (electron-rich and deficient rings), branched alkyl, cycloalkenyl, heterocycloalkyl- and other groups inspired in previously reported 11β-HSD1 inhibitors from Abbott (a series of dichoroaniline amides [ 18 ], and ABT-384, which contains a 4-(pyridin-2-yl)piperazin-1-yl ring system) [ 19 ].…”

“…Second, introduction of a phenyl group or few other aryl groups (either electron rich or electron-deficient, see compounds 7 or 5 , 10 , 11 , respectively) on the RHS of the molecule did not improve or was deleterious for the activity (IC 50 = 0.546 µM for RHS = phenyl, 4 ; 49% inhibition at 10 µM for RHS = 2-thiophenyl, 7 ; IC 50 = 4.3 µM for RHS = 2-pyridinyl, 5 ; and 0 and 23% inhibition at 10 µM for RHS = 4-chloro-3-pyridinyl, 10 , and RHS = 3-chloro-4-pyridinyl, 11 , respectively). Fortunately, when the phenyl group was substituted by a previously reported dichloroaniline group [ 17 ], the potency was substantially increased to deliver a low nanomolar inhibitor ( 8 , IC 50 = 0.045 µM). Third, introduction of N -substituted piperidinyl groups was again deleterious for the 11β-HSD1 inhibitory activity ( 12 and 13 , 3% and 0% inhibition at 10 µM, respectively).…”

Synthesis of propellanes containing a bicyclo[2.2.2]octene unitviathe Diels–Alder reaction and ring-closing metathesis as key steps

“…These results suggest that the bicyclo[2.2.2]octane amide derivatives t well into the hydrophobic pocket of 11b-HSD1. 8 In this regard, propellanes containing bicyclo[2.2.2]octene derivatives with enhanced hydrophobicity are worthy targets of investigation for human 11b-HSD1.…”

“…1). 8 The introduction of lipophilic substituents has proven to be a successful strategy to enhance the inhibition of 11b-HSD1 activity. IC 50 values of compounds 4-8 against 11b-HSD1 activity range from 0.02 to 0.03 mM.…”