OBE022, an Oral and Selective Prostaglandin F2{alpha} Receptor Antagonist as an Effective and Safe Modality for the Treatment of Preterm Labor [Drug Discovery and Translational Medicine]

Publication Date:
2018-07-07
Publisher:
The American Society for Pharmacology and Experimental Therapeutics
Print ISSN:
0022-3565
Electronic ISSN:
1521-0103
Topics:
Medicine
Published by:
http://www.aspet.org/
_version_ 1836399000203296768
autor Pohl, O., Chollet, A., Kim, S. H., Riaposova, L., Spezia, F., Gervais, F., Guillaume, P., Lluel, P., Meen, M., Lemaux, F., Terzidou, V., Bennett, P. R., Gotteland, J.-P.
beschreibung 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 F 2 α (PGF 2 α ) 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 2 α -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.
citation_standardnr 6300514
datenlieferant ipn_articles
feed_id 1930
feed_publisher The American Society for Pharmacology and Experimental Therapeutics
feed_publisher_url http://www.aspet.org/
insertion_date 2018-07-07
journaleissn 1521-0103
journalissn 0022-3565
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher The American Society for Pharmacology and Experimental Therapeutics
quelle Journal of Pharmacology and Experimental Therapeutics
relation http://jpet.aspetjournals.org/cgi/content/short/366/2/349?rss=1
search_space articles
shingle_author_1 Pohl, O., Chollet, A., Kim, S. H., Riaposova, L., Spezia, F., Gervais, F., Guillaume, P., Lluel, P., Meen, M., Lemaux, F., Terzidou, V., Bennett, P. R., Gotteland, J.-P.
shingle_author_2 Pohl, O., Chollet, A., Kim, S. H., Riaposova, L., Spezia, F., Gervais, F., Guillaume, P., Lluel, P., Meen, M., Lemaux, F., Terzidou, V., Bennett, P. R., Gotteland, J.-P.
shingle_author_3 Pohl, O., Chollet, A., Kim, S. H., Riaposova, L., Spezia, F., Gervais, F., Guillaume, P., Lluel, P., Meen, M., Lemaux, F., Terzidou, V., Bennett, P. R., Gotteland, J.-P.
shingle_author_4 Pohl, O., Chollet, A., Kim, S. H., Riaposova, L., Spezia, F., Gervais, F., Guillaume, P., Lluel, P., Meen, M., Lemaux, F., Terzidou, V., Bennett, P. R., Gotteland, J.-P.
shingle_catch_all_1 OBE022, an Oral and Selective Prostaglandin F2{alpha} Receptor Antagonist as an Effective and Safe Modality for the Treatment of Preterm Labor [Drug Discovery and Translational Medicine]
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 F 2 α (PGF 2 α ) 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 2 α -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.
Pohl, O., Chollet, A., Kim, S. H., Riaposova, L., Spezia, F., Gervais, F., Guillaume, P., Lluel, P., Meen, M., Lemaux, F., Terzidou, V., Bennett, P. R., Gotteland, J.-P.
The American Society for Pharmacology and Experimental Therapeutics
0022-3565
00223565
1521-0103
15210103
shingle_catch_all_2 OBE022, an Oral and Selective Prostaglandin F2{alpha} Receptor Antagonist as an Effective and Safe Modality for the Treatment of Preterm Labor [Drug Discovery and Translational Medicine]
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 F 2 α (PGF 2 α ) 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 2 α -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.
Pohl, O., Chollet, A., Kim, S. H., Riaposova, L., Spezia, F., Gervais, F., Guillaume, P., Lluel, P., Meen, M., Lemaux, F., Terzidou, V., Bennett, P. R., Gotteland, J.-P.
The American Society for Pharmacology and Experimental Therapeutics
0022-3565
00223565
1521-0103
15210103
shingle_catch_all_3 OBE022, an Oral and Selective Prostaglandin F2{alpha} Receptor Antagonist as an Effective and Safe Modality for the Treatment of Preterm Labor [Drug Discovery and Translational Medicine]
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 F 2 α (PGF 2 α ) 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 2 α -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.
Pohl, O., Chollet, A., Kim, S. H., Riaposova, L., Spezia, F., Gervais, F., Guillaume, P., Lluel, P., Meen, M., Lemaux, F., Terzidou, V., Bennett, P. R., Gotteland, J.-P.
The American Society for Pharmacology and Experimental Therapeutics
0022-3565
00223565
1521-0103
15210103
shingle_catch_all_4 OBE022, an Oral and Selective Prostaglandin F2{alpha} Receptor Antagonist as an Effective and Safe Modality for the Treatment of Preterm Labor [Drug Discovery and Translational Medicine]
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 F 2 α (PGF 2 α ) 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 2 α -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.
Pohl, O., Chollet, A., Kim, S. H., Riaposova, L., Spezia, F., Gervais, F., Guillaume, P., Lluel, P., Meen, M., Lemaux, F., Terzidou, V., Bennett, P. R., Gotteland, J.-P.
The American Society for Pharmacology and Experimental Therapeutics
0022-3565
00223565
1521-0103
15210103
shingle_title_1 OBE022, an Oral and Selective Prostaglandin F2{alpha} Receptor Antagonist as an Effective and Safe Modality for the Treatment of Preterm Labor [Drug Discovery and Translational Medicine]
shingle_title_2 OBE022, an Oral and Selective Prostaglandin F2{alpha} Receptor Antagonist as an Effective and Safe Modality for the Treatment of Preterm Labor [Drug Discovery and Translational Medicine]
shingle_title_3 OBE022, an Oral and Selective Prostaglandin F2{alpha} Receptor Antagonist as an Effective and Safe Modality for the Treatment of Preterm Labor [Drug Discovery and Translational Medicine]
shingle_title_4 OBE022, an Oral and Selective Prostaglandin F2{alpha} Receptor Antagonist as an Effective and Safe Modality for the Treatment of Preterm Labor [Drug Discovery and Translational Medicine]
timestamp 2025-06-30T23:36:01.004Z
titel OBE022, an Oral and Selective Prostaglandin F2{alpha} Receptor Antagonist as an Effective and Safe Modality for the Treatment of Preterm Labor [Drug Discovery and Translational Medicine]
titel_suche OBE022, an Oral and Selective Prostaglandin F2{alpha} Receptor Antagonist as an Effective and Safe Modality for the Treatment of Preterm Labor [Drug Discovery and Translational Medicine]
topic WW-YZ
uid ipn_articles_6300514