Synthesis and evaluation of a γ-lactam as a highly selective EP2 and EP4 receptor agonist

• Published in: Bioorganic & medicinal chemistry letters Vol. 18; no. 2; pp. 821 - 824
• Main Authors: YUFANG XIAO, LUCA ARALDI, Gian, ZHONG ZHAO, REDDY, Adulla, KARRA, Srinivasa, BRUGGER, Nadia, FISCHER, David, PALMER, Elizabeth, BAO, Bagna, MCKENNA, Sean D
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 15.01.2008
• Subjects: Animals; Biological and medical sciences; Female; Genital system. Reproduction; Guinea Pigs; Humans; Lactams - chemical synthesis; Lactams - pharmacokinetics; Lactams - pharmacology; Male; Medical sciences; Mice; Ovulation Induction; Pharmacology. Drug treatments; Receptors, Prostaglandin E - agonists; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP4 Subtype; Respiratory system; Structure-Activity Relationship; Agonist; EP2 prostanoid receptor; Intravenous administration; Rat; Lactam; Selectivity; Allylic compound; Guinea pig; Structure activity relation; Carboxylic acid; Subcutaneous administration; EP2 receptor; Secondary alcohol; Chemical synthesis; EP4 prostanoid receptor; Ovulation inducer; Prostaglandin; Bronchodilator; Rodentia; Benzene derivatives; Oral administration; In vitro; In vivo; Vertebrata; EP4 receptor; Mammalia; Mouse; Animal; Affinity; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.11.020

Gamma-lactam analogs (2) of EP(4) receptor agonists were identified by substitution of the pyrazolidinone ring (1) with a pyrrolidinone ring. Several compounds (such as 2a, 2h) with high potency, selectivity and acceptable PK profiles were discovered. These were assessed in animal models of ovulation induction and bronchoconstriction.