Discovery of a peroxisome proliferator activated receptor γ (PPARγ) modulator with balanced PPARα activity for the treatment of type 2 diabetes and dyslipidemia

Article abstract of DOI:10.1021/jm900367w

A series of 3-acylindole-1-benzylcarboxylic acids were designed and synthesized while searching for a PPARγ modulator with additional moderate intrinsic PPARα agonistic activity. 2-[3-[[3-(4-Chlorobenzoyl)-2-methyl- 6-(trifluoromethoxy)-1H-indol-1-yl]methyl]phenoxy]-(2R)-butanoic acid (12d) was identified as such an agent which demonstrated potent efficacy in lowering both glucose and lipids in multiple animal models with significantly attenuated side effects such as fluid retention and heart weight gain associated with PPARγ full agonists. The moderate PPARα activity of 12d not only contributed to the agent's ability to manage lipid profiles but also appears to have potentiated its PPARγ efficacy in lowering glucose levels in preclinical diabetic animal models.

Full text of DOI:10.1021/jm900367w

Supporting Information
Discovery of a Peroxisome Proliferator
Activated Receptor γ (PPARγ) Modulator
with Balanced PPARα Activity for the
Treatment of Type 2 Diabetes and
Dyslipidemia
Weiguo Liu, Kun Liu, Harold B. Wood, Margaret E. McCann, Thomas W. Doebber,
Ching H. Chang, Taro E. Akiyama, Monica Einstein, Joel P. Berger and Peter T. Meinke
Merck Research Laboratories, P. O. Box 2000, Rahway, New Jersey 07065
Table of Contents
1. Synthesis of optically active 2-bromoalkanecarboxylic acids:
2. Spectral and analysis data of compounds 15, 16, 17, 18
3. Results of elemental analysis of compounds 12c, 12d, 12g, 12h
S1

4. Chiral HPLC traces of selected compounds.
Synthesis of optically active 2-bromoalkanecarboxylic acids
(S)-2-Bromobutyric acid. A solution of (S)-2-aminobytyric acid (5 g, 48.5 mmol) and
potassium bromide (25 g, 194 mmol) in dilute aqueous sulfuric acid (2.5 N) was cooled
in an ice bath, and saturated aqueous solution of sodium nitrite (5 g, 72.8 mmol) was
added drop wise through an addition funnel in a period of about 4 h maintaining the
temperature of the solution below 5 oC. The mixture was then stirred at room temperature
for 1 h, and extracted with ethyl acetate (2 x 40 mL). The organic extracts were
combined, dried over anhydrous MgSO4, and concentrated to dryness to obtain 5.8 g
(72% yield) of the title compound as an oil. 1H NMR (CDCl3, 500 MHz) δ: 1.07 (t, 3H),
2.14 (dd, 2H), 4.13 (t, 1H). The optical purity of the product was accessed after its
conversion to 11d (see Experimental Section).
(S)-2-Bromobutyric acid, methyl ester. To avoid racemization, the ester was prepared
before immediate use. To a solution of (S)-2-bromobutyric acid (580 mg, 3.5 mmol) in
benzene : methanol (4:1, 10 mL) was added drop wise a solution of
(trimethylsilyl)diazomethane in hexane (2.0 M) until the bright yellow color generated in
the solution no longer dissipate. The mixture was then concentrated under vacuum to
dryness to obtain the title compound as an oil which was used immediately in the next
step for displacement reactions (see Experimental Section)
S2

(S)-2-Bromovaleric acid. Prepared from L-norvaline following the same procedure as
for (S)-2-bromobutyric acid. 1H NMR (CDCl3, 500 MHz) δ: 4.09 (t, 1H), 1.92 (m, 2H),
1.56 (m, 2H), 1.01 (t, 3H)
(S)-2-Bromo-4-methylvaleric acid. Prepared from L-valine following the same
procedure as for (S)-2-bromobutyric acid. 1H NMR (CDCl3, 500 MHz) δ: 4.23 (d, 1H),
2.25 (m, 1H), 1.05 (d, 6H).
Spectral and analysis data of compounds 15, 16, 17, 18 (see experimental section for
synthetic procedures)
Ethyl 2-(3-methylphenoxy)butyrate (15). 1H NMR (CDCl3, 500 MHz) δ: 7.27 (dd, 1H),
6.97 (d, 1H), 6.93 (s, 1H), 6.81 (d, 1H), 4.58 (t, 1H), 4.22 (q, 2H), 2.34 (s, 3H), 2.01 (m,
2H), 1.28 (t, 3H), 1.06 (t, 3H).
Ethyl 2-methyl-2-(3-methylphenoxy)butyrate (16). 1H NMR (CDCl3, 500 MHz) δ: )
7.25 (dd, 1H), 6.96 (d, 1H), 6.92 (s, 1H), 6.81 (d, 1H), 4.21 (q, 2H), 2.33 (s, 3H), 2.45 (s,
3H), 1.85 (m, 2H), 1.28 (t, 3H), 0.95 (t, 3H).
Ethyl 2-methyl-2-(3-bromomethylphenoxy)butyrate (17). 1H NMR (CDCl3, 500 MHz)
δ: 7.26 (t, 1H), 7.01 (d, 1H), 6.95 (s, 1H), 6.82 (d, 1H), 4.46 (s, 2H), 4.25 (q, 2H), 2.44
(s, 3H),1.86 (m, 2H), 1.29 (t, 3H), 0.95 (t, 3H).
S3

Results of elemental analysis of compound 12c, 12d, 12g, 12h.
compound
formula
calculated
found
C%
H%
4.25
4.25
4.50
4.50
C%
H%
4.25
4.28
4.45
4.48
C28H23ClF3NO5
C28H23ClF3NO5
C29H25ClF3NO5
C29H25ClF3NO5
61.60
61.60
62.20
62.20
61.72
61.67
62.25
62.31
12c
12d
12g
12h
S4

Chiral HPLC traces of selected compounds:
S5

S6

S7

S8

S9

S10