Application of a 3,3-diphenylpentane skeleton as a multi-template for creation of HMG-CoA reductase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.05.100

Based on our hypothesis that the 3,3-diphenylpentane (DPP) skeleton is useful as a multi-template for creation of various biologically active compounds and acts as a steroid skeleton substitute, we designed and synthesized novel HMG-CoA reductase inhibitors with a DPP skeleton. Among them, sodium (E,3R,5S)-7-(2-(4-fluorophenyl)-4-(3-phenylpentan-3-yl)phenyl)-3,5-dihydroxy-hept-6-enoate showed potent HMG-CoA reductase-inhibitory activity comparable with that of clinically useful mevastatin.

Full text of DOI:10.1016/j.bmcl.2009.05.100

Bioorganic & Medicinal Chemistry Letters 19 (2009) 4228–4231
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Application of a 3,3-diphenylpentane skeleton as a multi-template
for creation of HMG-CoA reductase inhibitors
Shinnosuke Hosoda a, Daisuke Matsuda b, Hiroshi Tomoda b, Mariko Hashimoto a, Hiroshi Aoyama a,
Yuichi Hashimoto a,
*
a Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
b Gradute School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Based on our hypothesis that the 3,3-diphenylpentane (DPP) skeleton is useful as a multi-template for
creation of various biologically active compounds and acts as a steroid skeleton substitute, we designed
and synthesized novel HMG-CoA reductase inhibitors with a DPP skeleton. Among them, sodium
(E,3R,5S)-7-(2-(4-fluorophenyl)-4-(3-phenylpentan-3-yl)phenyl)-3,5-dihydroxy-hept-6-enoate showed
potent HMG-CoA reductase-inhibitory activity comparable with that of clinically useful mevastatin.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 8 May 2009
Revised 21 May 2009
Accepted 25 May 2009
Available online 29 May 2009
Keywords:
3,3-Diphenylpentane
DPP skeleton
HMG-CoA reductase
Statin
Biologically active compounds with a 3,3-diphenylpentane
(DPP) skeleton include vitamin D3 agonists, such as LG190178 (1)
(Fig. 1).1,2 We have been engaged in structural development stud-
ies of DPP-type vitamin D3 agonists, and found that potent andro-
gen antagonists, including DPP-0113 (2) (Fig. 1), can be created
based on the DPP skeleton.3,4 This led us hypothesize that the
DPP skeleton can be employed as a steroid skeleton substitute,
and we have verified this idea by creating progesterone antago-
nists, such as compound 3 (Fig. 1), farnesoid X receptor (FXR) ago-
nists (whose cognate ligands include chenodeoxycholic acid), such
as DPPF-01 (4) (Fig. 1), and peroxisome proliferator-activated nu-
clear receptor (PPAR) agonists, including DPPK-01 (5) (Fig. 1).
Moreover, we showed that the DPP skeleton can be a superior scaf-
fold for creating not only nuclear receptor ligands, but also steroid-
(Fig. 1), have been created by using this approach, although steroi-
dal anti-BVDV agents have not been reported as far as the authors
know.7,11,12 Overall, anyway, these results confirm the usefulness
of the DPP skeleton as a multi-template for creation of various bio-
logically active compounds, and therefore, we planned to apply the
DPP skeleton as a scaffold for fragment-based drug design (FBDD)
and as a structure for creation of a focused chemical library.
We chose 3-hydroxy-3-methylglutaryl coenzyme A reductase
(HMG-CoA reductase: HMGR) as the target molecule. HMGR is
the rate-controlling enzyme in cholesterol biosynthesis, and is
the target molecule of statins. An elevated level of low-density
lipoprotein-cholesterol (LDL-C) is one of the key risk factors for
atherosclerosis and coronary heart disease (CHD).13,14 Statins, such
as mevastatin (compactin, 8), rosuvastatin (9), fluvastatin (10),
atorvastatin (11) and pitavastatin (12) (Fig. 2), inhibit HMGR and
reduce LDL-C levels in the bloodstream.15–18 Many synthetic stat-
ins have been developed, and the structural requirements seem
well established, that is, almost all of the synthetic statins, includ-
ing rosuvastatin (9), fluvastatin (10), atorvastatin (11) and pita-
vastatin (12), possess (A) a 3-desmethylmevalonic acid moiety
(MA part), (B) a 4-fluorophenyl group (FPh part) and (C) a bulky
hydrophobic group such as an isopropyl group or a cyclopropyl
group as pharmacophores. Therefore, we require a scaffold onto
which functional groups A–C can be introduced for preparing novel
HMGR inhibitors. In this connection, some steroids are known to
inhibit HMGR,19,20 and oxysterols possessing a hydroxyl group in
the side chain tend to show potent inhibition. So far, cholest-5-
ene-3b,25-diol (25-hydroxycholesterol, 13) (Fig. 2), a direct metab-
metabolizing enzyme inhibitors, including potent inhibitors of 5a-
reductase (whose cognate substrates include testosterone), such as
compound 6 (Fig. 1).5–7
Furthermore, based on the idea that the number of protein fold
structure types that comprise all the domains occurring in human
proteins is quite limited (there may be only ca. 1000 fold struc-
tures) in spite of the huge number of human proteins (50,000–
70,000 unique amino acid sequences),8–10 we expected that the
DPP skeleton would afford a superior scaffold to create various bio-
logically active compounds.11 Indeed, potent anti-bovine viral diar-
rhea viral (BVDV) agents, including compound DPP-0111 (7)
* Corresponding author. Tel.: +81 3 5841 7847; fax: +81 3 5841 8495.
E-mail address: hashimot@iam.u-tokyo.ac.jp (Y. Hashimoto).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.05.100

S. Hosoda et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4228–4231
4229
Figure 1. Typical biologically active compounds based on a 3,3-diphenylpentane skeleton.
Figure 2. Statin-type and oxysterol-type HMGR inhibitors.
olite of cholesterol in the liver, is the most potent inhibitor among
reported oxysterols. Since the DPP skeleton is considered to act as a
steroid substitute and a multi-template as mentioned above, we
decided to use the DPP skeleton as a scaffold upon which to display
the moieties A, B and C, with the aim of creating novel HMGR
inhibitors.
We first planned to use one of the phenyl rings of the DPP skel-
eton as the FPh part by introducing fluorine, and also planned to
introduce the MA part into the other phenyl ring of the DPP skele-
ton, that is, compounds 14a–e, to create candidate DPP-type HMGR
inhibitors. Compounds 14a–e were prepared according to Scheme 1.
Starting from ethyl fluorobenzoate 15a–d, the diethyl moiety and
phenol group were introduced, and then the phenolic hydroxyl
group of 17a–e was converted to triflate (18a–e). A desmethylm-
evalonic acid moiety, as the organotin derivative 19 (Stille cou-
pling) or the boronate ester 20 (Suzuki coupling), was coupled
with triflates 18a–e to afford 21a–e. Finally, deprotection of acetal
and tert-butyl ester by means of acidic and basic hydrolysis affor-
ded 14a–e as sodium salts.21–25
and 10 mg protein of microsomal fraction was incubated at 37 °C for
30 min. The reaction was terminated by addition of 2 M HCl aq and
the metabolites were converted to mevalonolactone. The metabolite
mixture was separated by means of thin layer chromatography
(Merck 20 TLC plates Silica Gel 60 F254) with acetone/benzene (1:1
v/v). The radioactivity of each spot on the plate was measured with
a bioimaging analyzer (FLA-7000, Fuji Film, Japan).
In screening using method A, 14a showed no apparent HMGR-
inhibitory activity even at 100 mM under the experimental
conditions used (Table 1). However, compound 14b containing
an isopropyl group at the R4 position showed slight inhibitory
activity with IC50 values of 26 and 2.2 mM in methods A and B,
respectively. This one order of magnitude difference in the IC50 val-
ues can be attributed to the difference of substrate concentration
between methods A and B. Possibly because 14b is a competitive
inhibitor, the measured IC50 values are dependent on the concen-
trations of the substrate and enzyme. The appearance of HMGR-
inhibitory activity in 14b but not in 14a suggests that a bulky
hydrophobic moiety be required as a substituent group R4 for the
activity. Next, the effect of the position of the fluoro group on the
terminal phenyl ring on the activity was investigated. Compared
with the para-fluoro derivative 14b, the meta-fluoro derivative
The inhibitory potency of the prepared compounds toward rat
HGMR was evaluated by the method described previously.26 Briefly,
DL-[3-14C]HMG-CoA (3.7 MBq in method A or 0.37 MBq in method B)

4230
S. Hosoda et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4228–4231
Scheme 1. Reagents and conditions: (a) EtMgBr, THF, 16 h, 61–95%; (b) 2-R4-phenol, H2SO4 aq, 1 h; (c) Tf2O, DIPEA, CH2Cl2, 0 °C, 4 h, 59–87% (two steps); (d) 18a–b,
PdCl2(PPh3)2, PPh3, LiCl, DMF, 80 °C, 6 h; (e) 18c–e, Pd(PPh3)4, K3PO4, DMF–H2O, 65 °C, 6 h; (f) HCl aq, THF, 14–34% (two steps); (g) NaOH aq, THF, 38–97%.
Table 1
SAR for HMGR inhibition (1)
Compound
R1
R2
R3
R4
IC50
(
l
M) Method A
IC50
2.2
(lM) Method B
14a
14b
14c
14d
14e
F
F
H
H
H
H
H
F
H
H
H
H
H
F
H
Inactive
26
92
i-Pr
i-Pr
i-Pr
i-Pr
7.4
1.8
H
Mevastatin (8)
Fluvastatin (10)
0.04
0.003
14c and ortho-fluoro derivative 14d showed less potent inhibition.
However, the non-substituted derivative 14e possessed similar
activity to 14b, suggesting that the effect of para-fluoro substitu-
tion is negligible, that is, the para-fluorophenyl moiety does not
function as a FPh part.
Therefore, we next introduced the FPh part at another position.
Based on the structure of 14e and other synthetic statins, we de-
signed compounds possessing another phenyl group 25a27 and
fluorophenyl group 25b–d,28–30 and synthesized them by methods
similar to that used for the preparation of 14e (Scheme 2).
Scheme 2. Reagents and conditions: (a) 2-phenylphenol, H2SO4 aq, 1 h, quant; (b) phenol, H2SO4 aq, 1 h, 90%; (c) NBS, CH3CN, 61%; (d) phenylboronic acid, Pd(PPh3)4, Na2CO3,
DME–H2O, reflux, 7 h, 70–82%; (e) Tf2O, DIPEA, CH2Cl2, 0 °C, 4 h; (f) 20, Pd(PPh3)4, K3PO4, DMF–H2O, 65 °C, 6 h; (g) HCl aq, THF, 13–23% (three steps); (h) NaOH aq, THF, 41–
56%.

S. Hosoda et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4228–4231
4231
Table 2
SAR for HMGR inhibition (2)
8. Koonin, E. V.; Wolf, Y. I.; Karev, G. P. Nature 2002, 420, 218.
9. Grishin, N. V. J. Struct. Biol. 2001, 134, 167.
10. Koch, M. A.; Wittenberg, L.-O.; Basu, S.; Jeyaraj, D. A.; Gourzoulidou, E.;
Reinecke, K.; Odermatt, A.; Waldmann, H. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
16721.
11. Hosoda, S.; Hashimoto, Y. Mini-Rev. Med. Chem. 2009, 9, 572.
12. Hosoda, S.; Aoyama, H.; Goto, Y.; Salim, M. T. A.; Okamoto, M.; Baba, M.;
Hashimoto, Y. Bioorg. Med. Chem. Lett. 2009, 19, 3157.
13. De, D.; Khanna, I. Annu. Rep. Med. Chem. 2007, 42, 177.
14. Tobert, J. A. Nat. Rev. Drug Disc. 2003, 2, 517.
15. Endo, A.; Kuroda, M.; Tsujita, Y. J. Antibiot. 1976, 29, 1346.
16. Brown, A. G.; Smale, T. C.; King, T. J.; Hasenkamp, R.; Thompson, R. H. J. Chem.
Soc., Perkin Trans. 1 1976, 1165.
Compound
R4
IC50 (lM) Method B
14e
25a
25b
25c
25d
i-Pr
Ph
2-F-Ph
3-F-Ph
4-F-Ph
1.8
0.85
0.82
1.2
17. Davidson, M. H. Expert Opin. Investig. Drug 2002, 11, 125.
18. Desager, J. P.; Horsmans, Y. Clin. Pharmacokinet. 1996, 31, 348.
19. Kandutsch, A. A.; Chen, H. W. J. Biol. Chem. 1974, 249, 6057.
20. Parish, E. J.; Parish, S. C.; Li, S. Crit. Rev. Biochem. Mol. Biol. 1999, 34, 265.
21. (E,3R,5S)-7-(4-(3-(4-Fluorophenyl)pentan-3-yl)phenyl)-3,5-dihydroxyhept-6-
enoic acid (14a). 1H NMR (500 MHz, DMSO) d 7.30 (d, J = 8.1 Hz, 2H), 7.15 (dd,
J = 8.5, 5.6 Hz, 2H), 7.08–7.04 (m, 4H), 6.45 (d, J = 15.9 Hz, 1H), 6.17 (dd,
J = 15.9, 6.4 Hz, 1H), 4.26 (q, J = 6.4 Hz, 1H), 3.84–3.80 (m, 1H), 2.21–2.18 (m,
1H), 2.07–2.02 (m, 5H), 1.63–1.58 (m, 1H), 1.48–1.44 (m, 1H), 0.61 (t, J = 7.3 Hz,
6H); HRMS (FAB, m/z, M+) calcd for C24H29FO4, 400.2050; found 400.2033.
22. (E,3R,5S)-7-(4-(3-(4-Fluorophenyl)pentan-3-yl)-2-isopropylphenyl)-3,5-dihydroxy-
hept-6-enoic acid (14b). 1H NMR (500 MHz, DMSO) d 7.28 (d, J = 8.6 Hz, 1H),
7.15 (dd, J = 9.0, 5.6 Hz, 2H), 7.07 (t, J = 9.0 Hz, 2H), 7.01 (d, J = 1.7 Hz, 1H), 6.86
(dd, J = 8.6, 1.7 Hz, 1H), 6.79 (d, J = 15.8 Hz, 1H), 6.00 (dd, J = 15.8, 6.2 Hz, 1H),
4.31–4.26 (m, 1H), 3.92–3.88 (m, 1H), 3.20 (sept, J = 6.8 Hz, 1H), 2.28 (dd,
J = 14.5, 4.7 Hz, 1H), 2.16–2.13 (m, 1H), 2.04 (q, J = 7.3 Hz, 4H), 1.66–1.60 (m,
1H), 1.54–1.49 (m, 1H), 1.10 (d, J = 6.8 Hz, 6H), 0.55 (t, J = 7.3 Hz, 6H); HRMS
(FAB, m/z, [M+Na]+) calcd for C27H35FNaO4, 465.2417; found 465.2433.
23. Sodium (E,3R,5S)-7-(4-(3-(3-fluorophenyl)pentan-3-yl)-2-isopropylphenyl)-3,5-
0.15
As shown in Table 2, all the compounds thus prepared (25a–d)
showed more potent HMGR-inhibitory activity than 14e. Espe-
cially, the para-fluorophenyl group-bearing analog 25d showed
the most potent activity, having an IC50 value of 0.15 mM (mea-
sured by method B), among the compounds prepared. Introduction
of a fluoro group at the para-position seems to be quite effective,
that is, the para-fluoro analog shows an almost one order of mag-
nitude lower IC50 value compared to the ortho- and meta-fluoro
regioisomers (IC50 values of 0.82–1.2 mM measured by method
B). Introduction of a fluoro group at only the para-position of 25a
(i.e., 25d) resulted in an increase of the activity. Introduction at
the ortho-position (25b) had almost no effect on the activity, and
introduction at the meta-position (25c) resulted in a decrease of
the activity.
dihydroxyhept-6-enoate (14c). 1H NMR (500 MHz, DMSO)
d 7.31–7.27 (m,
2H), 7.02 (d, J = 1.2 Hz, 1H), 6.99–6.91 (m, 3H), 6.86 (dd, J = 7.9, 1.2 Hz, 1H),
6.77 (d, J = 15.9 Hz, 1H), 6.01 (dd, J = 15.9, 6.1 Hz, 1H), 4.28 (q, J = 6.7 Hz, 1H),
3.81–3.76 (m, 1H), 3.18 (sept, J = 6.7 Hz, 1H), 2.07–2.03 (m, 5H), 1.95–1.91 (m,
1H), 1.62–1.56 (m, 1H), 1.48–1.43 (m, 1H), 1.10 (d, J = 6.7 Hz, 6H), 0.55 (t,
J = 7.3 Hz, 6H); MS (FAB, [MÀNa+H]+) m/z 443.
In conclusion, we obtained the potent HMGR inhibitor 25d with
an IC50 value comparable to that of mevastatin 8 (the relative po-
tency of 25d vs mevastatin (8) is approximately 0.3), by employing
the DPP skeleton as a scaffold upon which to array the pharmaco-
phore structures known to be required for statins (i.e., the MA part
and FPh part). Although the structure of 25d is not outside the gen-
eral range of structures of known synthetic statins, our results sug-
gest that the DPP skeleton is indeed useful as a core scaffold for
fragment-based drug design and creation of focused chemical li-
braries, and also as a multi-template for creation of analogs of ste-
roidal bioactive compounds. These results further support the
validity of the multi-template hypothesis6,12,31 as a technique for
the design of novel biologically active compounds.
24. Sodium (E,3R,5S)-7-(4-(3-(2-fluorophenyl)pentan-3-yl)-2-isopropylphenyl)-3,5-
dihydroxyhept-6-enoate (14d). 1H NMR (500 MHz, DMSO) d 7.50 (t, J = 7.9 Hz,
1H), 7.29–7.24 (m, 2H), 7.20 (t, J = 7.3 Hz, 1H), 6.98–6.94 (m, 2H), 6.81 (d,
J = 7.9 Hz, 1H), 6.77 (d, J = 15.9 Hz, 1H), 6.00 (dd, J = 15.9, 6.1 Hz, 1H), 4.28 (q,
J = 6.7 Hz, 1H), 3.83–3.80 (m, 1H), 3.16 (sept, J = 6.7 Hz, 1H), 2.15–2.10 (m, 3H),
2.06–1.97 (m, 3H), 1.63–1.57 (m, 1H), 1.50–1.45 (m, 1H), 1.06 (d, J = 6.7 Hz,
6H), 0.54 (t, J = 7.3 Hz, 6H); HRMS (FAB, m/z, [M+H]+) calcd for C27H35FNaO4,
465.2417; found 465.2421.
25. Sodium (E,3R,5S)-7-(4-(3-phenylpentan-3-yl)-2-isopropylphenyl)-3,5-dihydroxy-
hept-6-enoate (14e). 1H NMR (500 MHz, DMSO) d 7.28–7.24 (m, 3H), 7.15–
7.13 (m, 3H), 7.02 (s, 1H), 6.85 (d, J = 9.8 Hz, 1H), 6.76 (d, J = 15.9 Hz, 1H), 6.00
(dd, J = 15.9, 5.5 Hz, 1H), 5.02 (br, 1H), 4.28 (q, J = 6.1 Hz, 1H), 3.75–3.70 (m,
1H), 3.20–3.15 (m, 1H), 2.05 (q, J = 7.3 Hz, 4H), 2.01 (dd, J = 15.6, 3.1 Hz, 1H),
1.81 (dd, J = 15.6, 8.5 Hz, 1H), 1.59–1.53 (m, 1H), 1.40 (dt, J = 14.0, 6.1 Hz, 1H),
1.09 (d, J = 6.7 Hz, 6H), 0.55 (t, J = 7.3 Hz, 6H); HRMS (FAB, m/z, [MÀNa+H]+)
calcd for C27H36O4, 424.2614; found 424.2600.
26. Tomoda, H.; Kumagai, H.; Tanaka, H.; Omura, S. Biochim. Biophys. Acta 1987,
922, 351.
Acknowledgements
27. Sodium
(E,3R,5S)-7-(2-phenyl-4-(3-phenylpentan-3-yl)phenyl)-3,5-dihydroxy-
hept-6-enoate (25a). 1H NMR (500 MHz, DMSO) d 7.52 (d, J = 8.5 Hz, 1H), 7.41
(t, J = 7.3 Hz, 2H), 7.35–7.12 (m, 6H), 7.08 (dd, J = 7.9, 1.8 Hz, 1H), 7.00 (d,
J = 1.8 Hz, 1H), 6.41 (d, J = 15.9 Hz, 1H), 6.12 (dd, J = 15.9, 6.1 Hz, 1H), 5.02 (br,
1H), 4.15 (q, J = 6.7 Hz, 1H), 3.79–3.72 (m, 1H), 2.09 (q, J = 7.3 Hz, 4H), 1.76-
1.73 (m, 2H), 1.60–1.43 (m, 2H), 0.58 (t, J = 7.3 Hz, 6H); HRMS (FAB, m/z,
[MÀNa+H]+) calcd for C30H34O4, 458.2457; found 458.2430.
We thank Kaneka Corporation for a generous gift of tert-butyl
(3R,5S)-6-hydroxy-3,5-O-isopropylidene-3,5-dihydroxyhexanoate.
The work described in this paper was partially supported by
Grants-in-Aid for Scientific Research from The Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan, and the Japan
Society for the Promotion of Science.
28. Sodium
(E,3R,5S)-7-(2-(2-fluorophenyl)-4-(3-phenylpentan-3-yl)phenyl)-3,5-
dihydroxy-hept-6-enoate (25b). 1H NMR (500 MHz, CDCl3) d 7.45 (d, J = 8.5 Hz,
1H), 7.24–7.07 (m, 10H), 7.03 (t, J = 8.5 Hz, 1H), 6.37 (d, J = 15.7 Hz, 1H), 6.03
(dd, J = 15.7, 7.0 Hz, 1H), 4.33 (m, 1H), 4.18 (m, 1H), 2.38 (m, 2H), 2.09 (q,
J = 7.3 Hz, 4H), 1.67 (m, 1H), 1.51 (m, 1H), 0.62 (t, J = 7.3 Hz, 6H); HRMS (FAB,
m/z, [M+H]+) calcd for C30H33FNaO4, 499.2261; found 499.2282.
References and notes
29. Sodium
(E,3R,5S)-7-(2-(3-fluorophenyl)-4-(3-phenylpentan-3-yl)phenyl)-3,5-
dihydroxy-hept-6-enoate (25c). 1H NMR (500 MHz, CDCl3) d 7.25–6.94 (m,
12H), 6.50 (d, J = 15.9 Hz, 1H), 6.09 (m, 1H), 4.41 (m, 1H), 4.28 (m, 1H), 2.47 (m,
2H), 2.11 (q, J = 7.3 Hz, 4H), 1.73 (m, 1H), 1.60 (m, 1H), 0.58 (t, J = 7.3 Hz, 6H);
HRMS (FAB, m/z, [M+H]+) calcd for C30H33FNaO4, 499.2261; found 499.2231.
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30. Sodium
(E,3R,5S)-7-(2-(4-fluorophenyl)-4-(3-phenylpentan-3-yl)phenyl)-3,5-
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d
7.45 (d,
J = 9.2 Hz, 1H), 7.25–7.14 (m, 6H), 7.09–7.04 (m, 5H), 6.50 (d, J = 15.9 Hz, 1H),
6.07 (dd, J = 15.9, 6.7 Hz, 1H), 4.47–4.43 (m, 1H), 4.29–4.25 (m, 1H), 2.11 (q,
J = 7.3 Hz, 4H), 1.78–1.73 (m, 2H), 1.65–1.61 (m, 2H), 0.63 (t, J = 7.3 Hz, 6H);
HRMS (FAB, m/z, [MÀNa+H]+) calcd for C30H33FO4, 476.2363; found 476.2365.
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