Optimization of amide-based EP3 receptor antagonists.
Prostaglandin E receptor subtype 3 (EP3) antagonism may treat a variety of symptoms from inflammation to cardiovascular and metabolic diseases. Previously, most EP3 antagonists were large acidic ligands that mimic the substrate, prostaglandin E2 (PGE2). This manuscript describes the optimization of a neutral small molecule amide series with improved lipophilic efficiency (LipE) also known as lipophilic ligand efficiency (LLE) ((a) Nat. Rev. Drug Disc.2007, 6, 881; (b) Annu. Rep. Med. Chem.2010, 45, 380).
Worldwide Medicinal Chemistry, Pfizer Worldwide Research & Development, Cambridge, MA 02139, United States. Electronic address: esther.lee2@pfizer.com.
Esther C Y
EC
Lee
Worldwide Medicinal Chemistry, Pfizer Worldwide Research & Development, Cambridge, MA 02139, United States.
Kentaro
K
Futatsugi
Worldwide Medicinal Chemistry, Pfizer Worldwide Research & Development, Groton, CT 06340, United States.
Joel T
JT
Arcari
Worldwide Medicinal Chemistry, Pfizer Worldwide Research & Development, Groton, CT 06340, United States.
Kevin
K
Bahnck
Worldwide Medicinal Chemistry, Pfizer Worldwide Research & Development, Groton, CT 06340, United States.
Steven B
SB
Coffey
Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research & Development, Groton, CT 06340, United States.
David R
DR
Derksen
Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development, Cambridge, MA 02139, United States.
Amit S
AS
Kalgutkar
Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research & Development, Groton, CT 06340, United States.
Paula M
PM
Loria
Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research & Development, Groton, CT 06340, United States.
Raman
R
Sharma
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000577:Amides; C545647:PTGER3 protein, human; D058308:Receptors, Prostaglandin E, EP3 Subtype
EP3 receptor; GPCR; Indazole; LipE; Metabolites; P-gp; PGE2