2
Z. Yang et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
Fig. 2. The target compounds.
MBX-2982, DS-8500a, BMS-903452, LEZ763, ZYG-19) as shown in
Fig. 1.
Analogs 27a–t were evaluated for their abilities to activate the
human GPR119 in a cell-based cAMP assay, which were expressed
in EC50 and %max values. The EC50 values represent the concentra-
tion of the tested compounds for 50% cAMP stimulation of oleoy-
lethanolamide (OEA), while the %max values present the relative
response (%) of the tested compounds compared to the maximal
2
4–30
In our efforts to discover small molecule full agonist of
GPR119, pyrimidine compound AR231453 was selected as lead
structure. As disclosed in our previously papers, derivatives 1
and 2 bearing endo-nortropanol/amine exhibited strong and full
GPR119 agonistic activities (EC50 in the nanomolar range,
4
1
effect of OEA.
3
1,32
Fig. 2).
Based on the exciting results, optimization of lead
Table 1 illustrated the biological results of compounds 27a–t.
Among these analogs, compounds bearing 2-fluoro-4-methylsul-
fonyl aniline group showed more potent GPR119 activation activ-
ities than 4-methylsulfonylaniline group. And most compounds
synthesized from endo-azabicyclic moiety exhibited superior
EC50 values and stronger agonistic activities comparing with
those containing exo-azabicyclic moiety. Especially, compounds
27c, 27i, 27m, 27n, 27q, 27r, 27s, 27t displayed strong EC50s (sin-
gle digit nM). However, derivatives 27c, 27n, 27r, 27s, 27t were
observed middle level %max values and proved as partial ago-
nists. Moreover, several derivatives only with endo-azabicyclic
scaffold were proved as full agonists basted on %max values. Fur-
thermore, compound 27q bearing endo-azabicyclic amine 11
revealed the potent EC50 value (1.8 nM) with good efficacy
(104.3% max). And compound 27m containing endo-azabicyclic
alcohol showed the quite good efficacy (112.2% max) with best
EC50 value (1.2 nM).
compound was conducted via retaining 5-nitropyrimidine and
replacing piperidine with conformation restricted diverse azabi-
cyclic ethers or amines. We estimated that introduction of rigid
fragments like endo/exo azabicyclic rings to the ligands that
reduced the conformational flexibility to make an ideal conforma-
tion and best recognition by the receptor. Herein, we report syn-
thesis of a series of 5-nitropyrimidine derivatives with endo/exo
azabicyclic fragments as potential GPR119 agonists for the treat-
ment of type 2 diabetes.
The azabicyclic intermediates 3–12 were synthesized follow-
ing the procedures and conditions as shown in Scheme 1. The
Diels-Alder reaction of cyclopentadiene, ammonium chloride
and formaldehyde in water gave alkene compound, which was
then protected by a Boc group. Transformation of alkene 13 into
a mixture of alcohol 3 and 4 was achieved using a hydrobora-
tion-oxidation reaction. Amines 5–8 were prepared from alcohols
3
and 4 via a 3 steps sequence of PCC oxidation followed by
In summary, we discovered a new series of 5-nitropyrimidine
analogs with diverse aza-bicyclic ether or amine as GPR119
gonists for treatment of type 2 diabetes. As a result, most
derivatives exhibited the significant GPR119 activation activities.
All compounds containing 2-fluoro-4-methylsulfonyl aniline
fragment showed more potent GPR119 agonistic activities than
those with 4-methylsulfonylaniline group, which indicated fluo-
rine atom as a hydrogen bond receptor was benefit for the acti-
vation activity. And analogs bearing endo-azabicyclic scaffold
exhibited better %max values and were proved as full agonists
comparing with exo-azabicyclic moiety, which implied that
endo-azabicyclic moiety might be ‘‘agonist conformation”. It is
exciting that compounds 27c, 27i, 27m, 27n, 27q, 27r, 27s,
27t displayed single digit nM of EC50 Values. Notably, the analog
27q showed potent agonistic activity (104.3% max) with strong
EC50 value (1.8 nM) while the analog 27m revealed maximum
agonistic activity (112.2% max) with quite good EC50 value
(1.2 nM). These results encourage us to search other heterocyclic
structures as parents ring with endo-azabicyclic moiety to inves-
tigate the structure activity relationship of ligands with GPR119.
The follow-up studies and results will be reported in due
course.
33,34
reductive amination and debenzylation.
The azabicyclic rings
9–12 were generated from ketone 20 via similar methods with
intermediates 3–8. The ketone 20 was obtained by the aza
Diels-Alder reaction, which was converted to compound 21
via replacement of p-methoxyphenyl group (PMP) with Boc
3
5
3
6
group. Reduction of 21 with NaBH
and 10 with a ratio of 1.2/1. The synthetic pathway of amines
1–12 was same with 5–8 by reductive amination and debenzy-
lation. The stereochemistry of all intermediates 3–12 was deter-
4
gave a mixture alcohol 9
1
1
33–37
mined based on H NMR data and published procedures.
The methyne contiguous with nitrogen or oxygen in bicyclic
configuration isomers showed different splitting signal in
NMR spectra.
1
H
The synthesis of 5-nitropyrimidine analogs 27a–t was outlined
in Scheme 2. 4,6-Dichloro-5-nitropyrimidine, 4-methylsulfony-
laniline and 2-fluoro-4-methylsulfonylaniline were prepared
according to previously reported procedures.3
8–40
Reaction of
4
,6-dichloro-5-nitropyrimidine and substituted aniline in DMF
yielded compounds 25 and 26, following by treatment with
diverse azabicyclic alcohol or amine to afford target compounds
2
7a–t.
Yang, Zunhua
