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3121
absorption and good BBB penetration.9 Compound 28 was also pro-
gressedtorati.v. pharmacokinetics, andshowedmoderateclearance
(Cl 34 ml/min/kg) and low volume of distribution (Vd 1.5 L/kg) after
bolus solution dosing (0.3 mg/kg).
The remaining concern with the pyrrolo-imidazoles was a1A
Emax, which was viewed to be too high at 70–80%.10 The Letter
immediately following this one11 will detail how a1A Emax was
reduced and EC50 activity was increased, whilst retaining the
desired ADME and CNS drug-like properties of 28.
2. Musselman, D. M.; Ford, A. P. D. W.; Gennevois, D. J.; Harbison, M. L.; Laurent, A.
L.; Mokatrin, A. S.; Stoltz, R. R.; Blue, D. R. BJU Int. 2004, 93, 78.
3. Whitlock, G. A.; Conlon, K.; McMurray, G.; Roberts, L. R.; Stobie, A.; Thurlow, R.
J. Bioorg. Med. Chem. Lett. 2008, 18, 2930.
4. Conlon, K.; Christy, C.; Whitlock, G. A.; Roberts, L. R.; Stobie, A.; Thurlow, R. J.;
McMurray, G. J. Pharmacol. Exp. Ther., submitted for publication.
5. Roberts, L. R.; Bryans, J.; Conlon, K.; McMurray, G.; Stobie, A.; Whitlock, G. A.
Bioorg. Med. Chem. Lett. 2008, 18, 6437.
6. In a recent review of
a1-receptor agonists, no N-alkylated imidazolines or
imidazoles were described. Bishop, M. J. Curr. Topics Med. Chem. 2007, 7, 135.
7. CAUTION should be exercised in the handling of nitro compounds. DSC analysis
was determined on all alkyl nitro analogues 18. If an exotherm was observed at
>200 °C then the RaNi conditions at 100 °C were deemed to be safe. For
analogues with DSC exotherms at <200 °C the more ambient SnCl2 conditions
were employed.
Acknowledgements
8. In silico molecular modeling calculated
a 0.8 kcal/mol energy difference
We would like to thank Alison Bridgeland for screening data;
Debbie Lovering, Edward Pegden, Danny Ho, Katherine England,
Rachel Osborne, Simon Wheeler and Helen Mason for compound
synthesis. We also thank Peter Bungay for ADME assessment of
compounds 10–29.
between axial and equatorial conformations of 5. This energy gap is well
within the typical 5 kcal/mol difference observed for bound versus low energy
conformations reported in the literature, see: Perola, E.; Charifson, P. S. J. Med.
Chem. 2004, 47, 2499.
9. Wang, Q.; Rager, J. D.; Weinstein, K.; Kardos, P. S.; Dobson, G. L.; Li, J.; Hidalgo, I.
J. Int. J. Pharm. 2005, 288, 349.
10. The Roche clinical agent Ro 115-1240 had an Emax of 60% in our hands, which
was in line with published data, see Blue, D. R.; Daniels, D. V.; Gever, J., R.; Jett,
M. F.; O’Yang, C.; Tang, H. M.; Williams, T. J.; Ford, A. P. D. W. BJU Int. 2004, 93,
162. Ro 115-1240 was reported not to cause cardiovascular effects at the dose
tested in the clinic, see Ref. 2.
References and notes
1. (a) Hieble, J. P.; Bylund, D. B.; Clarke, D. E.; Eikenburg, D. C.; Langer, S. Z.;
Lefzowitz, R. J.; Minneman, K. P.; Ruffolo, R. R., Jr. Pharmacol. Rev. 1995, 47, 267;
(b) Zhong, H.; Minneman, K. P. Eur. J. Pharmacol. 1999, 375, 261.
11. Roberts, L. R.; Brennan, P. E.; Fish, P. V.; Storer, R. I.; Whitlock, G. A. Bioorg. Med.
Chem. Lett. 2009, 19, 3113.