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Table 3
In vivo efficacy of compounds 16f and 16j in a thermoregulatory dysfunction modela
Compound
Maximum temperature reduction (°C)
Mean temperature reduction (°C)
Duration of action (h)
Onset of activity (h)
16f
16j
0
2.4
0
1.5
—
6
—
Immediate
a
Compounds were dosed po at 3 mg/kg; see Refs. 10 and 18 for details.
3. Chen, Z.; Skolnick, P. Expert Opin. Invest. Drugs 2007, 16, 1365.
4. Iversen, L. Br. J. Pharmacol. 2006, 147, S82.
supra)—were applied to the 3,4-dihydrosulfostyril ring system, a
slightly less polar scaffold (TPSA16 for 16a–l = 49.4). Incorporation
of these features afforded a new series of potent NRIs (Table 2). For
most analog pairs, a clear stereochemical preference was observed
for NET inhibition (eudismic ratios 6–18), except for trifluorinated
compounds 16k and 16l, where the enantiomers were equipotent.
Introduction of an ortho-fluoro group on the pendant phenyl ring
had a modest effect, but did provide up to a fourfold increase in
NET inhibition potency in the case of the unsubstituted core
(16a,b vs 16c,d); difluorination had a similar effect (16a,b vs 16e,f).
The metabolic stability of the dihydrosulfostyril series was
evaluated by measuring compound half-lives in rat liver microsomes.
Compounds 16a–f were found to be quickly metabolized (Table 2),
however, fluorination at the 6-position of the dihydrosulfostyril core
provided compounds (16g–l) that were generally highly stable under
the same assay conditions. This was consistent with a computational
prediction that the 6-position was the preferred site of CYP-mediated
oxidation.17 Aconsequenceofthe6-fluorosubstitution, however,was
a decrease in NRI/SRI selectivity. The 6-hydro compounds 16a–f were
highly selective for NET inhibition (ꢀ100-fold selectivity versus SERT
inhibition for available data), whereas the 6-fluoro analogs 16g–l
showed more modest NRI/SRI selectivity. The series as a whole was
also found to be highly selective for NET versus DAT inhibition.
The in vivo efficacy of compound 16j, which combines NET inhi-
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bition potency and microsome stability (IC50 = 0.011 lM, micro-
some t1/2 >30 min, Table 2), was studied in a thermoregulatory
dysfunction model. Norepinephrine stimulates areas of the hypo-
thalamus believed to regulate temperature, and NRIs have previ-
ously been reported to lower tail skin temperature (TST) in
ovariectomized rats.10,18 As is summarized in Table3, theTST of trea-
ted rats was lowered by up to 2.4 °C following oral administration of
3 mg/kg of 16j. Oral dosing of 16f, whichhas comparablein vitro NET
inhibition potency, produced no observed effect on TST, potentially
due to poor metabolic stability (microsome t1/2 = 4 min, Table 2).
In summary, two related series of norepinephrine reuptake
inhibitors were synthesized based on 3,4-dihydro-1H-2,1,3-benzo-
thiadiazine 2,2-dioxide or 3,4-dihydrosulfostyril cores and
screened for inhibition of monoamine reuptake. Structure–activity
relationships were determined for the series’ in vitro potency and
selectivity versus inhibition of serotonin and dopamine. Lead com-
pounds based on both cores were identified as potent and selective
NRIs, and 3,4-dihydrosulfostyril analog 16j, which was optimized
for both potency and stability, showed efficacy in a rat model of
thermoregulatory dysfunction.
10. Mahaney, P. E.; Gavrin, L. K.; Trybulski, E. J.; Stack, G. P.; Vu, A. T.; Cohn, S. T.;
Ye, F.; Belardi, J. K.; Santilli, A. A.; Sabatucci, J. P.; Leiter, J.; Johnston, G. H.; Bray,
J. A.; Burroughs, K. D.; Cosmi, S. A.; Leventhal, L.; Koury, E. J.; Zhang, Y.;
Mugford, C. A.; Ho, D. M.; Rosenzweig-Lipson, S. J.; Platt, B.; Smith, V. A.;
Deecher, D. C. J. Med. Chem. 2008, 51, 4038.
Acknowledgements
The authors thank all colleagues whose work contributed to
the program described in this Letter: The Women’s Health &
Musculoskeletal Biology and Neuroscience departments provided
assay data; the Chemical Technologies group provided stability
data and chiral resolutions; the Structural Biology and Computa-
tional Chemistry group provided computational support.
11. For full experimental details see: Goldberg, J.; Fensome, A.; McComas, C. C.;
Zhang, P. WO 2008073958 A2.
12. Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.;
Combs, A. Tetrahedron Lett. 1998, 39, 2941.
13. Attempts at coupling (Scheme 1, step g) ortho-substituted phenylboronic acids
were unsuccessful.
14. For full experimental details, see: Fensome, A.; Goldberg, J. A.; McComas, C. C.;
Mann, C.W.;Melenski, E.G.;Sabatucci,J. P.;Woodworth,R.P.WO2008073956 A2.
15. Loev, B.; Kormendy, M. F.; Snader, K. M. J. Org. Chem. 1966, 31, 3531.
16. Ertl, P.; Rohde, B.; Selzer, P. J. Med. Chem. 2000, 43, 3714.
References and notes
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