A. D. Adams et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3185–3190
3189
of substitution on the alpha phenyl ring of 10 is repor-
ted in Table 3.
signs of PPARg mechanism based toxicity, would be
that the efficacy in the rodent DM2 model is driven
largely by PPARa activation. This phenomenon has
been reported by both Glaxo and Boehringer-Man-
nheim scientists for GW957814 and BM17.0744.15 In the
case of BM 17.0744, the same favorable ratio of efficacy
to PPARg mechanism based toxicity is reported. The
mechanism of this efficacy is under active investigation
in rodents.
Simple para substitution of 10 improved bioavailability
consistently to ꢃ80% for 14, 17 or 18 with good effi-
cacy in the db/db model and a modest increase in affi-
nity for PPARg. Effects on potency and receptor
selectivity were modest. All para substituted analogues
showed a trend to increased affinity for PPARg. Any
efficacy correlation to this increased PPARg activation
could easily be masked by small exposure differences in
this set. What fraction of the efficacy is contributed by
PPARg driven effects is perhaps best judged by tracking
the PPARg driven side effects.
Acknowledgements
We would like to thank Dr. Gerard Kieczykowski,
Amanda Makarewicz and Glenn Reynolds for supplies
of starting materials. Additional technical support for
biological evaluation was provided by; Margaret Wu,
John Ventre, Chhabi Biswas and Neelam Sharma.
The mechanism-based side effects seen with PPARg
agonists are clinically significant. Weight gains up to 12
pounds over one year with pioglitazone and over 9
pounds with rosiglitazone are seen. Incidence of edema
is up to 16% in pioglitazone combination therapy and
8.4% in rosiglitazone therapy. Side effects are serious
enough to limit the clinical use of PPARg agonist in
some DM2 patients.18 These and further mechanism
based effects are faithfully recapitulated in normal rats.3
Additional effects in rodents include plasma volume
expansion, brown adipose tissue (BAT) proliferation
and significant increases in heart weight.
References and Notes
1. Berger, J.; Moller, D. E. Annu. Rev. Med. 2002, 53, 409.
2. An excellent review, Willson, T. M.; Brown, P. J.; Stern-
bach, D. D.; Henke, B. R. J. Med. Chem. 2000, 43, 527. An
update in 2001 including a list of PPAR agonists in develop-
ment for diabetes, Sorbera, L. A.; Leeson, L.; Martin, L.;
Castaner, J. Drugs Future 2001, 26, 354. Recent examples of
PPARg/a mixed agonists, Nomura, M.; Kinoshita, S.; Satah,
T.; Maeda, T.; Murakani, K.; Tsunoda, M.; Miyachi, H.;
Awano, K. Biorg. Med. Chem. Lett. 1999, 9, 533 (KRP-297).
3. For human data see: Tugwood, J. D.; Montague, C. T.
Hum. & Exper. Toxicol. 2002, 21, 429. For BRL49653 (rosi-
glitazone) in rodents see: Pickavance, L. C.; Tadayyon, M.;
Widdowson, P. S.; Buckingham, R. E.; Wilding, J. P. H. Br. J.
Pharmacol. 1999, 128, 1570.
4. FDC Reports Pink Sheet 7/10/2000, p20 10/29/2001.
5. Many studies with Bezafibrate show effects at the level of
FPG. Studies with fenofobrate and Gemfibrozil show effects
on OGTT or IGTT. Fenofibrate, B.; Idzior-Walus, B.; Sier-
adzki, J.; Rostworowski, W.; Zdzienicka, A.; Kawalec, E.;
Wojcik, J.; Zarnecki, B. J. G. Eur. J. Clin. Invest. 2000, 30,
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tardo, L.; Pacini, G.; Manzato, E.; Zambon, S.; Sacerdoti, D.;
de Kreutzenberg, S.; Piliego, T.; Tiengo, A.; Del Prato, S.;
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Sirtori, C.; Pazzucconi, F.; Bonfardeci, G.; Cimminiello, C.;
Notarbartolo, A.; Scafidi, V.; Bittolo Bon, G.; Alessandrini,
P.; Nenci, G.; Parise, P.; Colombo, L.; Piliego, T.; Tremoli, E.
Atherosclerosis 2000, 148, 397. At least 25 studies are reported
with Bezafibrate. For typical positive outcome studies see:
Ogawa, S.; Takeuchi, K.; Sugimura, K.; Fukuda, M. Metabo-
lism 2000, 49, 331. Rustemeijer, C.; Schouten, J. A.; Voerman,
H. J.; Hensgens, H. E. S.; Donker, A. J. M.; Heine, R. J.
Diabetes Metab. Resch. Revs. 2000, 16, 82. Alberti, K.; Jones,
I. R.; Laker, M. F.; Swai, A. B. M.; Taylor, R. J. Cardiovasc.
Pharm. 1990, 16, S21. Mikhailidis, D. P.; Mathur, S.; Barrads,
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A two-week assay was conducted to compare the man-
delate PPARa/g agonists to the same dose of the
PPARg agonist rosiglitazone for tolerability and lipid
lowering effects.10 Results are reported in Table 4. BAT
proliferation and heart weight increases were tracked as
the most sensitive markers of PPARg mediated toxicity.
Doses of one to three times the efficacious dose used in
the db/db DM2 model were used. Daily administration of
rosiglitazone (30 mkd) increased heart weight by 18–25%.
BAT depot mass was increased by 51–91%. Serum
chemistry values showed a decrease in TG but not
cholesterol with rosiglitazone, while the PPARa/g agonists
decreased both TG and cholesterol significantly for all
except one dose of compound 5. The co-regulated BAT
proliferation and heart weight increase phenomena
related to PPARg were not seen with any of the
PPARa/g agonists reported here. The most prominent
and unsurprising finding was a PPARa driven increase in
liver weight for all of the mandelate analogues tested.8
The mandelate PPAR agonists described here are char-
acterized by a PPARa selective to balanced PPARa/g
affinity and exceptional intrinsic efficacy in the PPAR-
aGAL4 chimer TA assay. These ortho, ortho- dis-
ubstituted arylmandelates are very effective at correcting
hyperglycemia in very insulin resistant db/db mice at
doses equal to or less than the clinically proven PPARg
selective insulin sensitizer, rosiglitazone. Both PPARa
selective and PPARa/g mixed mandelate agonists show
good efficacy. Pharmacokinetic parameters in SD rat
are consistently good to excellent for the series. Both
types of agonists are superior to rosiglitazone in a rat
tolerability model of the known, clinically relevant,
mechanism based toxicities caused by PPARg agonists.
The inference from the superior tolerability, without
6. Berger, J.; Leibowitz, M.; Doebber, T. W.; Elbrecht, A.;
Zhang, B.; Zhou, G.; Biswas, C.; Cullinan, C. A.; Hayes, N. S.;
Li, Y.; Tannen, M.; Ventre, J.; Wu, M.; Berger, G. D.; Mos-
ley, R.; Marquis, R.; Santini, C.; Sahoo, S. P.; Tolman, R.;
Smith, R. G.; Moller, D. E. J. Biol. Chem. 1999, 274, 6718.
Describes PPARGAL4 TA assays and the db/db mouse
model. Rosiglitazone is used as a full agonist (100%) reference