ObsEva SA, Plan-les-Ouates, Geneva, Switzerland (O.P., A.C., J.-P.G.); Imperial College London, Parturition Research Group, Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus, East Acton, London, United Kingdom (S.H.K., L.R., V.T., P.R.B.); Citoxlab, Evreux, France (F.S., F.G.); Porsolt Research Laboratory, Le Genest-Saint-Isle, France (P.G.); Urosphere SAS, Toulouse, France (P.L., M.M.); BioTrial, Rennes, France (F.L.); and André Chollet Consulting, Tannay, Switzerland (A.C.)
ObsEva SA, Plan-les-Ouates, Geneva, Switzerland (O.P., A.C., J.-P.G.); Imperial College London, Parturition Research Group, Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus, East Acton, London, United Kingdom (S.H.K., L.R., V.T., P.R.B.); Citoxlab, Evreux, France (F.S., F.G.); Porsolt Research Laboratory, Le Genest-Saint-Isle, France (P.G.); Urosphere SAS, Toulouse, France (P.L., M.M.); BioTrial, Rennes, France (F.L.); and André Chollet Consulting, Tannay, Switzerland (A.C.).
J Pharmacol Exp Ther. 2018 Aug;366(2):349-364. doi: 10.1124/jpet.118.247668. Epub 2018 May 18.
Preterm birth is the major challenge in obstetrics, affecting ∼10% of pregnancies. Pan-prostaglandin synthesis inhibitors [nonsteroidal anti-inflammatory drugs (NSAIDs)] prevent preterm labor and prolong pregnancy but raise concerns about fetal renal and cardiovascular safety. We conducted preclinical studies examining the tocolytic effect and fetal safety of the oral prodrug candidate OBE022 [()-2-amino-3-methyl-butyric acid ()-3-{[(S)-3-(biphenyl-4-sulfonyl)-thiazolidine-2-carbonyl]-amino}-3-(4-fluoro-phenyl)-propyl ester] and its parent OBE002 [()-3-(biphenyl-4-sulfonyl)-thiazolidine-2-carboxylic acid [(S)-1-(4-fluoro-phenyl)-3-hydroxy-propyl]-amide], both potent and highly selective antagonist of the contractile prostaglandin F (PGF ) receptor (FP). Efficacy of OBE022 and OBE002, alone and in combination with other tocolytics, was assessed in human tissues and pregnant animal models for inhibition of uterine contraction and delay of parturition. Selective safety of OBE022 and/or OBE002, compared with NSAID indomethacin, was assessed on renal function, closure of the ductus arteriosus, and inhibition of platelet aggregation. In in vitro studies, OBE002 inhibited spontaneous, oxytocin- and PGF -induced human myometrial contractions alone and was more effective in combination with atosiban or nifedipine. In in vivo studies, OBE022 and OBE002 reduced spontaneous contractions in near-term pregnant rats. In pregnant mice, OBE022 delayed RU486 [(8S,11R,13S,14S,17S)-11-[4-(dimethylamino)phenyl]-17-hydroxy-13-methyl-17-prop-1-ynyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one] -induced parturition and exerted synergistic effects in combination with nifedipine. OBE022 and/or OBE002 did not show the fetal side effects of ductus arteriosus constriction, impairment of kidney function, or inhibition of platelet aggregation observed with indomethacin. Orally active OBE022 and OBE002 exhibits potent tocolytic effects on human tissues ex vivo and animal models in vivo without causing the adverse fetal side effects seen with indomethacin. Selectively targeting the FP receptor in combination with existing tocolytics may be an effective strategy for preventing or delaying preterm delivery.
早产是产科的主要挑战，影响约 10%的妊娠。泛前列腺素合成抑制剂[非甾体抗炎药（NSAIDs）]可预防早产并延长妊娠时间，但对胎儿肾脏和心血管安全性存在担忧。我们进行了临床前研究，以检查口服前药候选物 OBE022[()-2-氨基-3-甲基丁酸 ()-3-[(S)-3-(联苯-4-磺酰基)-噻唑烷-2-羰基]-氨基]-3-(4-氟-苯基)-丙酯]及其母体 OBE002[()-3-(联苯-4-磺酰基)-噻唑烷-2-羧酸 [(S)-1-(4-氟-苯基)-3-羟基-丙基]-酰胺]的止吐作用和胎儿安全性，两者均为收缩性前列腺素 F（PGF）受体（FP）的有效且高度选择性拮抗剂。评估了 OBE022 和 OBE002 单独使用以及与其他止吐药联合使用时，在抑制子宫收缩和延迟分娩方面在人组织和妊娠动物模型中的功效。与 NSAID 吲哚美辛相比，评估了 OBE022 和/或 OBE002 的选择性安全性，包括肾功能、动脉导管关闭和血小板聚集抑制。在体外研究中，OBE002 单独抑制自发性、催产素和 PGF 诱导的人子宫收缩，与阿托西班或硝苯地平联合使用时更有效。在体内研究中，OBE022 和 OBE002 减少了接近足月的妊娠大鼠的自发性收缩。在怀孕的小鼠中，OBE022 延迟了 RU486[（8S,11R,13S,14S,17S）-11-[4-（二甲基氨基）苯基]-17-羟基-13-甲基-17-丙炔基-1,2,6,7,8,11,12,14,15,16- 去甲雄甾烷-1,2,6,7,8,11,12,14,15,16- 去甲雄甾烷-3-酮]诱导的分娩，并与硝苯地平联合使用时具有协同作用。OBE022 和/或 OBE002 没有显示与吲哚美辛观察到的动脉导管收缩、肾功能损害或血小板聚集抑制相关的胎儿副作用。口服活性 OBE022 和 OBE002 在体外对人组织和体内动物模型均具有有效的抗吐作用，而不会产生与吲哚美辛相关的胎儿副作用。选择性针对 FP 受体并与现有的止吐药联合使用可能是预防或延迟早产的有效策略。
