Improving the developability profile of pyrrolidine progesterone receptor partial agonists

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Endocrinology

Background:

• Pyrrolidine-based progesterone receptor partial agonists showed high potency.
• These compounds exhibited liabilities such as hERG blockade and high volume of distribution.
• Modifications were needed to improve the safety profile of these agents.

Purpose of the Study:

• To synthesize and evaluate non-basic pyrrolidine derivatives as progesterone receptor partial agonists.
• To address liabilities associated with the basic pyrrolidine amine.
• To assess the in vivo efficacy of these modified compounds in an endometriosis model.

Main Methods:

• Chemical modification of the basic pyrrolidine amine to sulfonamide, carbamate, and amide functionalities.
• Assessment of the degree of partial agonism for the novel derivatives.
• In vivo efficacy testing in a validated animal model of endometriosis.

Main Results:

• Successfully converted basic pyrrolidine derivatives to non-basic analogs.
• Evaluated the partial agonism profile of the new chemical entities.
• Demonstrated therapeutic efficacy of the modified compounds in an in vivo endometriosis model.

Conclusions:

• Modification of the basic pyrrolidine amine successfully mitigated previously identified liabilities.
• The novel non-basic pyrrolidine derivatives retain partial agonism at the progesterone receptor.
• These findings support the potential of these improved compounds for endometriosis treatment.