OBE022, an Oral and Selective Prostaglandin F2α Receptor Antagonist as an Effective and Safe Modality for the Treatment of Preterm Labor.

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 [(S)-2-amino-3-methyl-butyric acid (S)-3-{[(S)-3-(biphenyl-4-sulfonyl)-thiazolidine-2-carbonyl]-amino}-3-(4-fluoro-phenyl)-propyl ester] and its parent OBE002 [(S)-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 F2α (PGF2α ) 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 PGF2α -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.

Differential Effects of Oxytocin Receptor Antagonists, Atosiban and Nolasiban, on Oxytocin Receptor-Mediated Signaling in Human Amnion and Myometrium.

One of the most established roles of oxytocin (OT) is in inducing uterine contractions and labor. Apart from inducing contractions, our recent studies showed that OT can also activate proinflammatory pathways in both human myometrial and amnion cells, which suggests that the proinflammatory role of OT should be taken into account when developing tocolytics targeting the OT/oxytocin receptor (OTR) system. The OTR antagonist, atosiban, is currently used therapeutically for the treatment of preterm labor. We previously showed that atosiban fails to inhibit the proinflammatory effects of OT in human amnion; atosiban alone activates nuclear factor-κB (NF-κB) and mitogen activated protein kinases, thus upregulating downstream prolabor genes. In contrast with our findings with atosiban, the presence of the orally active OTR antagonist, nolasiban, reduced the effect of OT on NF-κB and p38 kinase activation in both myometrial and amnion cells. Consistent with the activation of these inflammatory mediators, OT led to increases in the expression of cyclooxygenase-2 and phosphorylated cytosolic phospholipase A2, which was reflected in prostaglandin E2 synthesis. Inhibition of NF-κB activation by nolasiban also translated to suppression of downstream prolabor gene expression, such as cyclooxygenase-2, C-C motif chemokine ligand 2, interleukin-6, and interleukin-8. We also demonstrated that nolasiban treatment alone has no significant stimulatory effect on both the myometrium and amnion. In conclusion, our findings indicate that nolasiban possesses promising potential as a novel tocolytic agent for both acute and maintenance therapy, as it inhibits both myometrial contractions and the proinflammatory effects of OT without the biased agonist effects.

Canadian Trends in Free Flap Management for Microsurgical Lower Limb Reconstruction.

Introduction: Free tissue transfers have become a mainstay in lower limb salvage, allowing safe and reliable reconstruction after trauma, tumor extirpation, and complex wounds. The optimal perioperative (PO) management of these flaps remains controversial. This study aims to assess the current state of practice among Canadian microsurgeons. Methods: Sixty-four Canadian microsurgeons were approached to complete an online questionnaire regarding their PO management of fasciocutaneous free flaps used for lower limb reconstruction. Trends in dangling timing and duration, use of venous couplers, compressive garments, thromboprophylaxis, and surgeons' satisfaction with their protocol were assessed. Results: Twenty-eight surgeons responded. Fifty-seven percent did not have a specific mobilization protocol. Dangling was mainly initiated on postoperative days 5 to 6 (44%). The most common protocol duration was 5 to 6 days (43%). The concern for prolonged venous pooling was the main reason for delay of dangling (71%). Compressive garments were placed routinely by 12 surgeons (43%) with 20% starting before dangling, 46% with dangling, and 33% after dangling. Venous couplers were routinely used by 24 surgeons (85.7%). Trends in management were influenced by previous training in 53.6% of cases (vs evidence-based medicine 7.1%). Although 89.3% were satisfied with their approach, 92.8% would consider changing practice if higher-level evidence was available. Conclusions: The majority of Canadian microsurgeons initiate dangling early and utilize venous couplers. However, the use of compressive garments is limited. Trends in management are largely based on personal experience. Nearly all surgeons would consider changing their practice if higher-level evidence was available.

Introduction: Les transferts de tissus libres sont devenus une clé de voûte du sauvetage du membre inférieur, permettant une reconstruction sûre et fiable après un traumatisme, l'extirpation d'une tumeur et des blessures complexes. La gestion périopératoire optimale (PO) de ces volets reste controversée. Cette étude vise à évaluer l'état actuel des pratiques parmi les chirurgiens canadiens pratiquant la microchirurgie. Méthodes: Soixante-quatre spécialistes canadiens de microchirurgie ont été approchés et il leur a été demandé de répondre à un questionnaire en ligne sur leur gestion PO des lambeaux fascio-cutanés libres utilisés pour la reconstruction du membre inférieur. Les tendances concernant des échéances et des durées du protocole de jambe pendante, l'utilisation de coupleurs veineux, les vêtements compressifs, la thromboprophylaxie et la satisfaction des chirurgiens envers leur protocole ont été évaluées. Résultats: Vingt-huit chirurgiens ont répondu. Cinquante-sept pour cent (57 %) n'avaient pas de protocole de mobilisation précis. Le protocole de jambe pendante sans appui a été instauré aux jours postopératoires 5 ou 6 (44 %). La durée la plus courante du protocole était de 5 à 6 jours (43 %). La préoccupation d'une accumulation prolongée de sang veineux était la principale raison pour retarder l'exercice de jambe pendante (71 %). Douze (12) chirurgiens (43 %) ont mis en place de manière régulière des vêtements compressifs: 20 % d'entre eux ont commencé avant de laisser pendre le membre, 46 % en même temps et 33 % après avoir laissé pendre le membre. Des coupleurs veineux ont été utilisés en routine par 24 chirurgiens (85,7 %). Les tendances en matière de gestion ont été influencées par la formation antérieure dans 53,6 % des cas (contre la médecine fondée sur des données probantes: 7,1 %). Même si 89,3 % des chirurgiens étaient satisfaits de leur approche, 92,8 % d'entre eux envisageraient de modifier leur pratique si des données probantes de plus haut niveau étaient disponibles. Conclusions: La majorité des spécialistes canadiens de la microchirurgie instaurent précocement la mise en décharge hors du lit du membre inférieur et utilisent des coupleurs veineux. Cependant, l'utilisation de vêtements compressifs est limitée. Les tendances en matière de gestion reposent largement sur l'expérience personnelle. Presque tous les chirurgiens envisageraient de modifier leur pratique si des données probantes de plus haut niveau étaient disponibles.

The use of indocyanine green angiography in arterialized-venous free flaps: Case report and insight into flap vascular physiology.

Arterialized venous flaps (AVFs) are an innovative option in hand reconstruction. Their exact vascular physiology and survival mechanisms remain unclear. We report on two hand reconstruction cases with AVFs. Indocyanine green laser angiography was used to assess vascular perfusion of the flaps. A notable change in flap perfusion was seen by 48 h post-operatively with normalization of shunting and progression to a diffuse perfusion pattern resembling traditional flaps. Flap survival was attributed to reversed shunting at the microvascular level occurring within the first 48 h post-operatively.

Fine Details That Improve Nasal Reconstruction.

LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Identify common negative outcomes that arise with conventional nasal reconstruction. 2. Understand the technical refinements that help avoid and reduce negative outcomes in nasal reconstruction. 3. Learn about the utility of regional axial island flaps for nasal reconstruction, in particular, the lateral nasal artery flap. SUMMARY: Nasal reconstruction has been a preoccupation of surgeons dating to before 600 bc. The nose is the central focal point of the face and a key identifying facial feature, and surgery to the nose can prove to be challenging to even the most experienced surgeon. The objective of this CME article is to outline the most commonly used surgical options for each nasal aesthetic subunit, and the specific complications observed for each. The best surgical options and technical refinements are highlighted, and principles that may help restore the nose are outlined.

The Pediatric Arterialized Venous Flow-through Flap.

Arterialized venous flow-through flaps are solely vascularized through the venous plexus. The flaps were first described 40 years ago; however, reports of venous congestion and ischemia discouraged surgeons from adopting them into their armamentarium. Nevertheless, recent studies have demonstrated a resurgence of venous flow-through flaps for reconstruction of small to medium defects of the hand and digits. Although current data report variable levels of success in adults, no case reports have been published in the pediatric population for this type of flap. In this study, an arterialized venous flow-through flap from the medial forearm was used to reconstruct a volar hand defect in a young child. Flap markings, surgical technique, and aftercare are described. The surgery was uncomplicated, and the postoperative outcomes were aesthetically and functionally excellent. Venous flow-through flaps restore full-thickness defects, are relatively easy to perform, allow an early return to daily activities, and have almost no morbidity. These flaps offer excellent options for pediatric hand and finger defects.

Facial Transplantation in a Nationalized Health System: The Canadian Experience.

Facial transplantation (FT) is recognized as the ultimate reconstruction for severely disfigured patients. The substantial cost of these procedures in a nationalized health system has not been extensively published. The first Canadian FT performed in May 2018 was a great opportunity to address this subject and evaluate the viability of such a program. METHODS: A detailed patient chart review was performed and a cost per unit approach was used to estimate the procedure cost. The preoperative, operative, and the postoperative periods up to 1-year after the surgery were analyzed. Financial support from private sponsors and Hospital Fund donations were considered. The literature on international FT and national solid organ transplantation was reviewed. RESULTS: The overall 1-year cost was estimated at $440,224 (2018 CAD). The costs are explained by a long hospital length of stay, costly immunosuppressive therapy, and high immunosuppression-related complications. Those findings are consistent with international FT literature. The societal impact of the surgery was minimized with a $36,921 (2018 CAD) grant obtained from an external contributor. Interestingly, the hospital foundation sustained a 794% increase in donations ($1,787,148; 2019 CAD) the year following the surgery. CONCLUSION: Our experience confirmed that the combination of private funding, with positive goodwill and hospital donations, is a workable model for innovative surgery in the setting of a nationalized health system with financial restrictions.

Face Transplant: Current Update and First Canadian Experience.

SUMMARY: Facial vascularized composite allotransplantation has emerged as a groundbreaking reconstructive solution for patients with severely disfiguring facial injuries. The authors report on the first Canadian face transplant. A 64-year-old man sustained a gunshot wound, which resulted in extensive midface bony and soft-tissue damage involving the lower two-thirds of the face. In May of 2018, he underwent a face transplant consisting of Le Fort III and bilateral sagittal split osteotomies in addition to skin from the lower two-thirds of the face and neck. Virtual surgical planning was used to fabricate osteotomy guides and stereolithographic models. Microsurgical anastomoses of the facial (three branches) and infraorbital nerves were performed bilaterally. At 18-month follow-up, the aesthetic outcome was excellent. Partial restoration of light touch sensation had been observed over the majority of the allograft. Although significantly affected, animation, speech, mastication, and deglutition were continuously improving with intensive therapy. Nevertheless, the patient was now tracheostomy and gastrostomy free. Despite these limitations, he reported a high degree of satisfaction with the procedure and had reintegrated into the community. Four grade I episodes of acute rejection with evidence of endotheliitis were successfully treated. Postoperative complications were mainly infectious, including mucormycosis of the left thigh, treated with surgical resection and antifungal therapy. Undoubtedly, immunosuppression represents the greatest obstacle in the field and limits the indications for facial vascularized composite allotransplantation. Continuous long-term follow-up is mandatory for surveillance of immunosuppression-related complications and functional assessment of the graft.

Discovery of a novel series of CXCR3 antagonists.

The discovery of a novel series of CXCR3 antagonists is described. Starting from an HTS positive, iterative optimization gave potent compounds (IC(50) 15 nM in a chemotaxis assay). The strategy employed to improve the metabolic stability of these derivatives is described.

Oxytocin Receptor Antagonists, Atosiban and Nolasiban, Inhibit Prostaglandin F2α-induced Contractions and Inflammatory Responses in Human Myometrium.

Oxytocin receptor antagonists (OTR-A) have been developed as tocolytics for the management of preterm labour due to the significant role of oxytocin (OT) in the onset of both term and preterm labour. Similar to OT, prostaglandins (PGs) play key roles in myometrial contractility and cervical ripening. Inhibition of PG synthesis/activity is used to delay preterm birth. Thus, targeting the PG pathway in combination with an OTR-A may be an effective strategy for delaying preterm delivery. In this study, we examined the effects of atosiban and nolasiban on PGF2α-induced contractions and pro-inflammatory responses in human pregnant myometrium. Both OTR-As, atosiban and nolasiban, inhibited PGF2α-induced contractions in a dose-dependent manner (p < 0.001 and p < 0.01, respectively). These inhibitory effects involved the suppression of PGF2α-mediated increase in intracellular calcium levels. In addition, the OTR-As significantly suppressed PGF2α-induced activation of pro-inflammatory pathways such as NF-κB and mitogen activated protein kinases (MAPKs), and the subsequent expression of contraction-associated-protein, COX-2. We have demonstrated that atosiban and nolasiban not only inhibit contractions elicited by OT, but also inhibit contractions and inflammation induced by PGF2α. This suggests a possible crosstalk between OTR and PG receptor signalling and highlights the importance of understanding G protein-coupled receptor interactions/crosstalk in the development of future tocolytics.

Discovery of a new class of potent, selective, and orally bioavailable CRTH2 (DP2) receptor antagonists for the treatment of allergic inflammatory diseases.

A novel chemical class of potent chemoattractant receptor-homologous expressed on Th2 lymphocytes (CRTH2 or DP2) antagonists is reported. An initial and moderately potent spiro-indolinone compound ( 5) was found during a high-throughput screening campaign. Structure-activity relationship (SAR) investigation around the carboxylic acid group revealed that changes in this part of the molecule could lead to a reversal of functional activity, yielding weakly potent agonists. SAR investigation of the succinimide functional group led to the discovery of several single-digit nanomolar antagonists. The potency of these compounds was confirmed in a human eosinophil chemotaxis assay. Moreover, compounds ( R)- 58 and ( R)- 71 were shown to possess pharmacokinetic properties suitable for development as an orally bioavailable drug.

Arrest of preterm labor in rat and mouse by an oral and selective nonprostanoid antagonist of the prostaglandin F2alpha receptor (FP).

OBJECTIVE: The purpose of this study was to assess the tocolytic effect of AS604872, an orally active, potent, and selective prostanoid prostaglandin F2alpha receptor (FP) antagonist. STUDY DESIGN: Compound AS604872 was characterized and tested for its ability to block uterine contraction and delay preterm parturition in rodent models. RESULTS: AS604872 inhibited spontaneous uterine contractions in pregnant rat near term. In pregnant mouse, AS604872 delayed parturition induced by either the antiprogesterone RU-486 or the endotoxin lipopolysaccharide. Pups from treated mothers were delivered alive. The efficacy of AS604872 was superior to the beta-mimetic drug ritodrine. Combination of AS604872 and ritodrine showed an additive inhibitory effect on spontaneous uterine contractions in rat. CONCLUSION: A selective antagonist of the FP receptor suppresses uterine contractility and delays labor. Our findings identify a new potential modality for the pharmacological management of preterm labor.

Tocolytic effect of a selective FP receptor antagonist in rodent models reveals an innovative approach to the treatment of preterm labor.

BACKGROUND: Management of preterm labor by tocolysis remains an unmet medical need. Prostaglandins play a major role in regulation of uterine activity and in molecular mechanisms of human labor and parturition. There is some circumstantial evidence that prostaglandin F2alpha by action through the prostaglandin receptor subtype FP is effective in key events during labor uterine contraction, rupture of membranes and cervical dilation. This role of FP is briefly reviewed. In this study, we tested the hypothesis that an orally active and selective FP antagonist may arrest labor and delay parturition in animal models. METHODS: We examined the effects of a small molecule selective antagonist of the FP receptor (AS604872) in inhibition of spontaneous uterine contraction in pregnant rat near term. We tested AS604872 for its ability to delay preterm birth in a mouse model in which the anti-progestin agent RU486 triggered parturition. RESULTS: By oral or intravenous dosing AS604872 reduced markedly and dose-dependently the spontaneous uterine contractions in late-term pregnant rats at gestational days 19-21. In pregnant mice, AS604872 delayed the preterm birth caused by RU486 administration. The effect was dose-dependent with a significant increase in the mean delivery time of 16 and 33 hours at oral doses of 30 mg/kg and 100 mg/kg, respectively, in the case of labor triggered at gestational day 14. In both models AS604872 appeared more effective than the beta-agonist ritodrine. CONCLUSION: The tocolytic activity displayed by a selective FP receptor antagonist supports a key role for the FP receptor in the pathophysiology of premature birth and demonstrates the therapeutic potential of an FP antagonist for the treatment of preterm labor cases in which uterine hyperactivity plays a dominant role.

Factors Influencing the Rate of Post-Mastectomy Breast Reconstruction in a Canadian Teaching Hospital.

BACKGROUND: Post-mastectomy breast reconstruction (PMBR) improves psychosocial well-being, quality of life, and body image. Reconstruction rates vary widely (up to 42% in the United States), but the few Canadian studies available report rates of 3.8% to 7.9%. We sought to evaluate the current state of breast reconstruction in 1 Canadian teaching hospital and factors determining patients' access to reconstruction. METHODS: We performed a retrospective chart review of all patients with breast cancer undergoing mastectomy alone or mastectomy and reconstruction at a Canadian hospital between 2010 and 2013. We calculated rates of breast reconstruction and compared patient characteristics between the 2 groups, and then performed a multiple logistic regression to determine factors increasing the odds of receiving breast reconstruction. RESULTS: A total of 152 patients underwent 154 total or modified radical mastectomies. We obtained a rate of PMBR of 21%, 14% immediate reconstruction, and 8% delayed. Statistical analysis showed that compared to patients with mastectomy alone, patients who received PMBR were significantly younger, with a larger percentage having bilateral mastectomies, non-invasive breast cancer, and residing further from the hospital. Patients less than 50 years old and those with bilateral mastectomies had significantly greater odds of having a reconstruction. CONCLUSIONS: Our Canadian tertiary care institution has a high volume of breast surgery and an active breast reconstruction team. However, the rate of immediate reconstruction remains low compared to similar centers in the United States. We recommend a united effort to increase awareness regarding PMBR and address common misconceptions hindering patients' access to breast reconstruction. LEVEL OF EVIDENCE: Epidemiologic study, Level III.

HISTORIQUE: La reconstruction mammaire postmastectomie (RMPM) améliore le bien-être psychosocial, la qualité de vie et l'image corporelle. Le taux de reconstructions varie considérablement (jusqu'à 42 % aux États-Unis), mais les quelques études canadiennes signalent un taux de 3,8 % à 7,9 %. Les auteurs ont cherché à évaluer la situation relative aux reconstructions mammaires dans un hôpital universitaire canadien et les facteurs déterminant l'accès à la reconstruction. MÉTHODOLOGIE: Les chercheurs ont procédé à une analyse rétrospective des dossiers de toutes les patientes atteintes d'un cancer du sein qui avaient subi une simple mastectomie ou une mastectomie suivie d'une reconstruction dans un hôpital canadien entre 2010 et 2013. Ils ont calculé le taux de reconstructions mammaires et comparé les caractéristiques des patientes des deux groupes, puis ont procédé à une régression logistique multiple pour déterminer les facteurs qui accroissaient la probabilité de reconstruction mammaire. RÉSULTATS: Au total, 152 patients ont subi 154 mastectomies radicales totales ou modifiées. Les chercheurs ont obtenu un taux de RMPM de 21 %, soit 14 % de reconstructions immédiates et 8 % de reconstructions tardives. L'analyse statistique a révélé que, par rapport aux patientes qui avaient subi une simple mastectomie, celles qui avaient reçu une RMPM étaient considérablement plus jeunes, et un plus fort pourcentage avait subi une mastectomie bilatérale, était atteint d'un cancer du sein non invasif et habitait loin de l'hôpital. Les patientes de moins de 50 ans et celles qui avaient subi une mastectomie bilatérale couraient une plus grande chance de subir une reconstruction. CONCLUSIONS: Notre établissement de soins tertiaires canadien effectue un fort volume de chirurgies du sein et dispose d'une équipe de reconstruction mammaire active. Cependant, le taux de reconstructions immédiates demeure faible par rapport à celui de centres similaires aux États-Unis. Nous recommandons d'adopter un front uni pour mieux faire connaître la RMPM et calmer les erreurs courantes qui empêchent les patients d'avoir accès à la reconstruction mammaire. Qualité des preuves : Étude épidémiologique, niveau III.

Zygomatico-maxillary Reconstruction with Computer-aided Manufacturing of a Free DCIA Osseous Flap and Intraoral Anastomoses.

Craniomaxillofacial reconstruction using virtual surgical planning, computer-aided manufacturing, and new microsurgical techniques optimizes patient-specific and defect-directed reconstruction. A 3D customized free deep circumflex iliac artery (DCIA) flap with intraoral anastomoses was performed on a 23-year-old man with a posttraumatic right zygomatico-maxillary defect with failure of alloplastic implant reconstruction. An osseous iliac crest flap was sculpted based on a customized 3D model of the mirror image of the patient's unaffected side to allow for perfect fit to the zygomatico-maxillary defect. An intraoral dissection of the facial artery and vein was performed within the right cheek mucosa and allowed for end-to-end microvascular anastomoses. 3D preoperative planning and customized free DCIA osseous flap combined with an intraoral microsurgical technique provided restoration of facial esthetics and function without visible scars. In cases where zygomatico-malar reconstruction by alloplastic material fails, a customized free DCIA osseous flap can be designed by virtual surgical planning to restore facial appearance and function.

Effects of the Oral Oxytocin Receptor Antagonist Tocolytic OBE001 on Reproduction in Rats.

BACKGROUND: OBE001 is a novel, orally active nonpeptide oxytocin receptor antagonist under development for the treatment of preterm labor and improvement in embryo implantation and pregnancy rate in assisted reproductive technology (ART). The reproductive safety of OBE001 was evaluated in customized fertility embryonic development (FER)/early embryonic development (EED) and fetal development (FD) and pre/postnatal development (PPN) studies mimicking clinical exposure scenarios. METHODS: Oral OBE001 was evaluated at doses of 37.5, 75, and 125 mg/kg/d in female rats during a FER/EED study (from premating to implantation) and throughout FD during a FD/PPN study. RESULTS: No OBE001 effects were observed during the FER/EED study. The FD/PPN study did not result in adverse OBE001 effects in females allowed to litter, their offspring, and second-generation fetuses. Females at 125 mg/kg/d who underwent cesarean section before term had slight reductions in body weights and food consumption, and associated fetuses had slightly delayed ossification of skull bones, which was not adverse in the absence of effects on live offspring. CONCLUSION: OBE001 at up to 125 mg/kg/d had no effects on EED and no adverse effects on FD and postnatal development of rats. These results constitute an important step toward the development of OBE001 in preterm labor and ART indications.

Discovery and development of a new class of potent, selective, orally active oxytocin receptor antagonists.

We report a novel chemical class of potent oxytocin receptor antagonists showing a high degree of selectivity against the closely related vasopressin receptors (V1a, V1b, V2). An initial compound, 7, was shown to be active in an animal model of preterm labor when administered by the intravenous but not by the oral route. Stepwise SAR investigations around the different structural elements revealed one position, the arenesulfonyl moiety, to be amenable to structural changes. Consequently, this position was used to introduce a variety of substituents to improve the physicochemical properties. Some of the resulting analogues were found to be superior to 7 both in terms of potency in vitro and aqueous solubility, which translated into significantly improved efficacy in the animal model after intravenous and oral administration. The best compound, 73, potently inhibited oxytocin-induced uterine contractions in nonpregnant rats and reduced spontaneous uterine contractions in late-term pregnant rats.