M. Nomura et al. / Bioorg. Med. Chem. Lett. 22 (2012) 334–338
337
Table 6
Pharmacologic effects of (S)-4f in high-fat diet dogsa
Treatment
Body weight
(kg)
Food intake
(kg, cumulative value)
Triglycerides
(mg/dL)
Free fatty acid
(mEq/L)
Total cholesterol
(mg/dL)
non-HDL cholesterol
(mg/dL)
0.003 mg/kg
0.01 mg/kg
0.03 mg/kg
High-fat diet control
15.3 0.7
14.8 0.9
14.8 0.7
14.8 0.7
3.85 0.21
3.91 0.20
3.51 0.19
3.67 0.09
64 9⁄
48 8⁄
44 4⁄
0.607 0.074
0.651 0.071
0.576 0.066
0.624 0.057
190 10
176 7⁄
169 5⁄
65
8
50 5⁄
42 4⁄
98
4
205
6
75
5
a
Dogs fed on high-fat diet for 12 weeks were treated orally once a day for a week with (S)-4f (0.003, 0.01, 0.03 mg/kg/day), n = 6. Blood samples from dogs in the fed state
were analyzed for triglycerides, free fatty acid, total cholesterol, and non-HDL cholesterol. ⁄P < 0.05, significantly different vs. the control group.
Compound 4f has an asymmetric center at the 3-position of the
piperidine ring, and it is important to establish which stereochem-
istry at this position is required for activity. We therefore mea-
sured the potencies for the enantiomers of 4f. The enantiomers
of 4f were prepared from (R)- or (S)-1-tert-butoxycarbonyl-3-
aminopiperidine in the same manner as shown in Scheme 1.11
Acknowledgments
The authors wish to thank Dr. Y. Kohno, director of Kyorin Phar-
maceutical Co., Ltd for his helpful advice. The authors are also
grateful to M. Tsunoda, A. Iwane, and T. Ogata of Kyorin Pharma-
ceutical Co., Ltd for their technical assistance.
The S-isomer (S)-4f showed 150-fold higher PPARa activity than
the corresponding R-enantiomer (Table 2). With this information
in hand, we finally explored the SAR of the phenylthiazole group
(Table 3). The thiazole regioisomer 14a abrogated activity. The oxa-
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hydrogen, 4-fluoro, 4-methoxy and 4-nitro analogs (14c, 14f,
14h, 14i) decreased potency. However, replacement of the termi-
nal chloro substituent by a range of groups revealed substitution
of the terminal phenyl ring was well-tolerated compared to mod-
ification in the other regions.
Compound (S)-4f with potent PPARa activity and excellent sub-
type selectivity was evaluated for its species differences in PPAR
transactivation, as shown in Table 4. (S)-4f demonstrated a species
preference for human PPARa and PPARa transactivation activity of
(S)-4f was approximately 2-fold, 80-fold, 450-fold and 600-fold
more potent in humans than in dogs, hamsters, rats, and mice,
respectively.
The pharmacokinetic (PK) profile of (S)-4f was also investigated.
Results are summarized in Table 5. (S)-4f exhibited a good maxi-
mum concentration (Cmax = 315.7 ng/mL), good bioavailability
(F = 47.6%), and a long half life (t1/2 = 10 h) when administered or-
ally to rats at a dose of 1 mg/kg body weight. Administration to
dogs (0.3 mg/kg, po) also resulted in satisfactory PK parameters
(Cmax = 294.7 ng/mL, F = 73.1%, t1/2 = 74 h).
In light of the above species differences and PK results, com-
pound (S)-4f was evaluated in dogs fed on a high-fat diet for its
antidyslipidemic activity in vivo (Table 6). When administered or-
ally to high-fat diet dogs once a day for a week, (S)-4f (0.01, and
0.03 mg/kg) significantly lowered the serum levels of triglycerides,
total cholesterol, and non-HDL cholesterol without affecting body
weight and food intake. The finding that (S)-4f effectively lowered
triglyceride and total cholesterol levels in high-fat diet dogs sug-
gests that it will deliver a therapeutic benefit in the treatment of
dyslipidemia and atherosclerosis.
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In summary, a new series of cyclic amine-substituted benzoic
acid derivatives as PPARa agonists was identified, and their syn-
thesis and SARs were described. Among these compounds, (S)-4f
(KRP-105), which has progressed to clinical evaluation, showed po-
tent human PPARa transactivation activity and high subtype selec-
tivity. In addition, (S)-4f showed an excellent PK profile in both rats
and dogs, and effectively lowered triglyceride and total cholesterol
levels in high-fat diet dogs.
10. Experimental procedure for synthesis of 4f: (a) To
chlorophenyl)-4-methylthiazole-5-carboxylic acid (1.52 g, 5.99 mmol), 1-tert-
butoxycarbonyl-3-aminopiperidine (1.20 g, 5.99 mmol) and 1-
hydroxybenzotriazole monohydrate (1.10 g, 7.19 mmol) in DMF (20 mL) was
a mixture of 2-(4-