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involves the introduction of a bridge in the piperidine ring leading
to a puckered shape and a restriction in conformational flexibility
(Fig. 2). Herein, we report preliminary results of the synthesis and
evaluation of N-aryl and N-heteroaryl ABH derivatives as DPP-IV
inhibitors.
The requisite N-aryl and N-heteroaryl 3-azabicyclo [3.1.0]hex-
ane-6-amine intermediates were synthesized starting from the
known intermediate 1 (Scheme 1).5 Alkaline hydrolysis of the
amide 1 followed by protection of the resultant amine provided
the carbamate derivative 2. The removal of the N-benzyl group
was accomplished by catalytic hydrogenolysis. The ensuing amine
3 was coupled, in parallel, to a series of activated aryl and hetero-
aryl halides to afford the corresponding 3-(N-substituted)azabicy-
clo[3.1.0]hexan-6-amine derivatives (4a–w and 5a–o), which were
subsequently deprotected on treatment with TFA or pTSA to obtain
the corresponding amines (6a–w and 7a–o) in free or salt forms.
The chiral N-chloroacetyl-2-cyanopyrrolidine intermediate 9
was acquired following a one-step procedure from the known
intermediate 8 (Scheme 2).3d The compound 9 was subjected to
amination with various amine partners, 6a–w and 7a–o, to provide
the final compounds 10a–w and 11a–o (Tables 1 and 2).6 Two P1-
modified analogs (14 and 16) of the compound 11l were also
prepared from the respective known intermediates (13 and 15)
to explore additional SAR, as depicted in the Scheme 2.3a,d,6 Re-
cently, highly potent DPP-IV inhibitors with a des-cyanothiazoli-
dine at the P1 position have been identified.7
Scheme 2. Reagents and conditions: (a) ClCH2COCl, TEA, DCM; (b) 6a–w and 7a–o,
K2CO3, DMF (or TEA, DCM), RT; (c) 7l, K2CO3, DMF.
All compounds were tested in vitro for inhibitory activity
against soluble DPP-IV isolated from citrated human plasma.8
The DPP-IV inhibitors, which are non-selective against DASH
(DPP-IV activity and/or structural homolog) members, viz, DPP-2,
DPP-8 and DPP-9, have been implicated in species- and tissue-spe-
cific toxicities in preclinical studies.1a,9 Hence, selectivity against
DPP-2, DPP-8, and DPP-9 appears to be essential. The attenuation
of T-cell activation in vitro has been observed with DPP-8 and
DPP-9 inhibitors.9 Compounds with DPP-IV IC50 < 1000 nM were
assessed for selectivity against DPP-2, DPP-8, DPP-9, and PPCE.8
Furthermore, selected compounds were screened against other
DASH [APP and Prolidase] and related [APN and NEP] peptidases
and examined for effects on T-cell proliferation.8 NEP was included
in the selectivity panel because of safety concerns, as inhibition of
NEP enhances the incidence of life-threatening angioedema.10 NEP
like DPP-IV also degrades GLP-1.
The DPP-IV inhibitory activities of N-aryl (10a–w) and N-het-
eroaryl (11a–o, 14 and 16) ABH derivatives are listed in Tables 1
and 2. Since N-(4-cyanophenyl) piperidine derivatives have been
reported to be highly potent (Table 3),3f we investigated foremost
the activity of similar compounds by replacing the piperidine with
an ABH ring (10a–h). The 4-cyanophenyl derivative (10a) exhib-
ited moderate activity (165 nM). Further substitution with mixed
halides (–F and –Cl) at the 2- or 3-position was explored (10b–f).
While the 2-F group (10b) did not improve the activity (153 nM),
its 3-F isomer (10c) exhibited an improved activity (110 nM). The
3,5-difluoro substitution (10d) demonstrated an additive effect
and enhanced the activity by about 4-fold (38 nM) compared to
3-fluoro substitution (10c) alone (110 nM). Contrary to the fluoro
group, the chloro substitution had a reverse effect on activity. Thus,
while the –Cl group at the 2-position (10e) improved the activity
(95 nM), no significant improvement was noted at the 3-position
(10f). While the –CF3 group (10g) at the 2-position improved activ-
ity by ꢀ3-fold, it (10h) caused severe loss of activity at the 3-posi-
tion (42-fold). The replacement of nitrile in 4-cyanophenyl with
other electron withdrawing groups was also investigated. While
–COCH3 (10i) and –CONH2 (10k) groups imparted improvements
in activity, the –CO2Et (10j) group lowered the potency. The
replacement of –CONH2 (10k) with secondary amides –CONHMe
and –CONHCyPr (10l–m) was found to be detrimental to activity.
Activity could be optimized (2-fold) by relocating the –CN
group on the N-phenyl from the 4- to the 2-position (10a and
10n). Further substitution with a 3-Cl group (10o) enhanced the
activity resulting in the most potent compound (31 nM) in the N-
aryl series. While the 3-fluoro substitution (10r) depreciated the
activity by ꢀ2-fold, the 3,5-difluoro substitution (10u) resulted in
a further erosion of activity (ꢀ12-fold). The 2-cyanophenyl deriva-
tive (10n) had higher affinity than the 4-cyanophenyl derivative
(10a) and this effect was mirrored in compounds containing either
3-F, 3-Cl, or 3-CF3 group as additional substituents (cf. 10r, 10o,
10p vs 10c, 10f, 10h). However, the trend was reversed in the case
of isomeric pair with 3,5-difluoro substitution (10u and 10d). No
activity enhancement was realized by repositioning the –CN group
to 3-position (cf. 10v vs. 10c, 10r).
Scheme 1. Reagents and conditions: (a) i—NaOH, H2O-EtOH, 100 °C; ii—di-tert-
butyl dicarbonate, NaHCO3, H2O-dioxane; (b) H2 [50 psi], Pearlman’s catalyst, Me-
OH-THF; (c) aryl or heteroaryl halide (-F/-Cl/-Br), K2CO3, DMF, 100–140 °C; (d) TFA,
DCM or pTSA,MeCN.
Sattigeri, Jitendra A.
