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Table 1. Structure and in vitro profile of analogues 1-22AnalogueStructure a In vitro potency , EC 50( nM) at a receptorSelectivity vs.receptor bR 1 R 2 R 3 X Y hOT hV 2 hV 1a hV 2 hV 1a1 OH - (CH 2 ) 3 - S S 2.3 7.3 1 0 3 42 OMe - (CH 2 ) 3 - CH 2 S 0.70 170 41 c 240 5 8 c3 OMe - CH 2 - CH(OMe) - CH 2 - CH 2 S 0.98 690 >10000 d 700 >100 004 OMe H H CH 2 S 0.37 450 >1000 e 1200 >27005 OH n - Bu H S S 0.06 35 >10000 d 580 >1600006 OH n - Bu H CH 2 S 0.12 73 >10000 d 60 0 >830007 H n - Bu H CH 2 S 0.23 2000 >10000 d 8 6 00 >430008 OH 3 - MeBzl H S S 0.01 30 >10000 d 3000 >10000009 OH 3 - MeBzl H CH 2 S 0.08 210 >10000 d 2600 >12000010 OH 3 - MeBzl H S CH 2 0.02 55 71 2 7 00 3 5 0011 H 3 - MeBzl H S CH 2 0.56 1600 >10000 d 28 00 >1700012 OH 4 - FBzl H S S 0.01 82 >10000 d 8200 >100000013 OH 4 - FBzl H CH 2 S 0.08 330 >10000 d 4100 >12000014 OH 4 - FBzl H S CH 2 0.04 140 >10000 d 3500 >25000015 H 4 - FBzl H S CH 2 0.23 1400 >10000 d 6 0 00 >4300016 OH 2 - MeOEt H S S 0.03 80 >10000 d 2 6 00 >33000017 OH 2 - MeOEt H CH 2 S 0.11 70 >10000 d 630 >9000018 H 2 - MeOEt H CH 2 S 0.96 1100 >10000 d 1100 >1000019 H 2 - MeOEt H S CH 2 0.85 1300 >10000 d 1500 >1100020 OH Bzl H CH 2 S 0.04 140 >10000 d 3500 >25000021 OH 2 - PhEt H CH 2 S 0.04 160 >10000 d 4000 >25000022 OH 3 - HOPr H CH 2 S 0.01 500 >10000 d 50000 >1000000a For compound 1 R0 is NH 2 and for all other compounds is H; b Selectivity ratios are rounded down tothe nearest values with two significant figures; c partial agonist at the hV 1a R; d highest concentrationtested 10000 – nM ; e highest concentration tested - 1000 nMHOPr) showed a 70-fold gain in in vitro potency as compared to 2. The analogues where R 2was an arylalkyl (8-14, 20, 21) or hydroxyalkyl (22) displayed much desired improvementin selectivity versus the hV 2 R. The Phe 2 compounds 7, 11, 15, 18, 19 (R 1 = H) turned out tobe less potent as OT agonists and showed lower potencies at the hV 2 R than their Tyr 2counterparts thus resulting in similar selectivity profiles of the two series. All compounds3-22 displayed excellent selectivity versus hV 1a and hV 1b (data not shown) receptors withselectivity ratios exceeding 1000. The alterations to the disulfide bridge did not have asignificant impact on the overall in vitro pharmacological profile of these analogs.Based on overall favorable properties, compound 13, carba-1-[4-FBzlGly 7 ]dOT, hasbeen selected as a clinical candidate for use in peripheral indications including lactation. Inaddition, recent reports of CNS activities of oxytocin and oxytocin analogues, suggest thatcompound 13 could also be used to treat multiple central disorders.References1. Gimpl, G., Fahrenholtz, F. Physiol. Rev. 81, 629-683 (2001).2. Smith, J.G., Merrill, D.C. Clin. Obstet. Gynecol. 49, 594-608 (2006).3. Allen, M.J., Livermore, D.G.H., Mordaunt, J.E. Prog. Med. Chem. 44, 331-373 (2006).4. Morgan, D.B., et al. Br. J. Obstet. Gynaecol. 84, 6-12 (1977).5. Grzonka, Z., et al. J. Med. Chem. 26, 555-559 (1983).6. Fragiadaki, M., et al. Eur. J. Med. Chem. 42, 799-806 (2007).7. Weber, D., et al. J. Med. Chem. 46, 1918-1930 (2003).8. Peters, N.C., Duvekot, J. J. Obstet. Gynecol. Surv. 64, 129-135 (2009).307