Drug discovery strategies for the identification of novel regulators of uterine contractility

Abstract

Preterm birth and postpartum hemorrhage are the leading causes of neonatal and maternal morbidities worldwide, respectively. Current clinically utilized tocolytics and uterotonics to manage these obstetric conditions are limited due to their off-target effects and/or lack of efficacy. Thus, an ideal tocolytic or uterotonic would be uterine-selective with rapid onset and long-duration efficacy. Here, we discuss strategies for the discovery of new therapeutic targets and compounds that regulate uterine contractility with the aforementioned properties.

Figure 1

Drug discovery pipeline. The first-step is to identify a target or phenotypic-pathway for high-throughput screening of compound libraries. Once ‘hit’-compounds are identified, a series of secondary screening assays allow prioritization based on potency, target-selectivity and ex vivo efficacy. Lead hit-compounds can undergo optimization through or structure-activity-relationship or ADMET (absorption, distribution, metabolism, excretion and toxicity) studies. Finally, pre-clinical animal testing for in vivo efficacy, drug distribution and off-target effects.

Figure 2

General timeline for pre-clinical testing of drugs on timing of delivery in mouse pregnant models. (a) Test-tocolytics are administered once or twice daily either before, concomitant or post-injection of lipopolysaccharide (LPS) or mifepristone (RU486), commonly used for induction of preterm birth. In mice, normal (untreated) wildtype term delivery occurs between gestational day 19–20, depending on the mouse strain, thus preterm delivery is usually defined as delivery occurring 24 hours prior (~day18) or within 24 hours of normal LPS/RU486-induced preterm delivery (<day 17). (b) Test-uterotonics are administered before the last gestational day for their ability to induce preterm delivery. (c) In order to evaluate whether a test-drug significantly affected the timing of delivery, through its effect on uterine contractility without adverse maternal or fetal consequences, outcomes of interest can be experimentally evaluated.