Synthesis of 5‐ and 7‐hydroxy indolizidin‐2‐one prostaglandin‐F_2α modulators and activity on myometrial contractility towards development of agents for delaying preterm birth

Abstract

In pursuit of more effective-labor delaying tocolytic agents, the prostaglandin F2α (PGF2α) receptor (FP) modulator PDC113.824 [(6S)-2] represents a potent lead for developing therapy to treat preterm birth. Derivatives of FP modulator (6S)-2 were synthesized, possessing respectively 5-and 7-hydroxyl groups on the indolizidin-2-one amino acid (I 2 aa) residue. The effects of the alcohol substituents were examined in a PGF2α-induced myometrial contraction assay. Based on knowledge of dihedral angle values of model I 2 aa peptides from X-ray analyses, the results of the study indicate respectively encouraging and limited potential for creating improved tocolytic agents by modifications at the 5-and 7-positions.indolizidin-2-one amino acids, peptidomimetics, preterm birth, prostaglandin-F2α receptor, tocolytic | INTRODUCTIONPreterm birth (PTB), parturition before 37 weeks of gestation, is associated with high mortality and morbidity rates. 1 An unmet medical urgency, PTB has some of the most expensive healthcare expenditures per patient. [2][3][4] Each year, about 15 million babies are born prematurely globally, resulting in 1.1 million deaths, most of which occur in low-and middle-income countries. 1,5 Tocolytic drugs are currently used to block uterine contractions and delay preterm labor, but have shown marginal efficacy and may cause adverse effects for both the mother and the fetus. 6 Novel therapies to treat