title: New, potent, and selective peptidic oxytocin receptor agonists.
abstract: Mothers of preterm babies frequently have difficulty establishing or maintaining lactation, thought to be due to interference with the milk ejection reflex. Administration of exogenous oxytocin can produce alveolar contraction and adequate breast emptying resulting in establishment of successful lactation. The natural hormone oxytocin is not receptor-selective and may cause hyponatremia via V2 receptor mediated antidiuresis. We have designed a series of potent oxytocin analogues containing N-alkylglycines in position 7 with excellent selectivity versus the related V1a, V1b, and V2 vasopressin receptors and short half-life: agonists 31 ([2-ThiMeGly(7)]dOT), 47 (carba-6-[Phe(2),BuGly(7)]dOT), 55 (carba-6-[3-MeBzlGly(7)]dOT), and 57 (carba-1-[4-FBzlGly(7)]dOT) have EC50 values at hOTR < 0.1 nM, selectivity ratios versus related human vasopressin receptors of >2000, IC50 at hV1aR > 500 nM, and total clearance in rats in the range of 60-80 mL min(-1) kg(-1). Compound 57 (FE 202767) is currently in clinical development for the treatment of preterm mothers requiring lactation support.
authors.affiliation: Ferring Research Institute Inc. , 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Kazimierz
authors.initials: K
authors.lastname: Wiśniewski
authors.forename: Sudarkodi
authors.initials: S
authors.lastname: Alagarsamy
authors.forename: Robert
authors.initials: R
authors.lastname: Galyean
authors.forename: Hiroe
authors.initials: H
authors.lastname: Tariga
authors.forename: Dorain
authors.initials: D
authors.lastname: Thompson
authors.forename: Brian
authors.initials: B
authors.lastname: Ly
authors.forename: Halina
authors.initials: H
authors.lastname: Wiśniewska
authors.forename: Steve
authors.initials: S
authors.lastname: Qi
authors.forename: Glenn
authors.initials: G
authors.lastname: Croston
authors.forename: Regent
authors.initials: R
authors.lastname: Laporte
authors.forename: Pierre J-M
authors.initials: PJ
authors.lastname: Rivière
authors.forename: Claudio D
authors.initials: CD
authors.lastname: Schteingart
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D017930:Genes, Reporter; D006801:Humans; D008297:Male; D009842:Oligopeptides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D010121:Oxytocin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D018045:Receptors, Oxytocin / Q000819:agonists* / Q000235:genetics; D017483:Receptors, Vasopressin / Q000819:agonists / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D009842:Oligopeptides; D010456:Peptides, Cyclic; D018045:Receptors, Oxytocin; D017483:Receptors, Vasopressin; C000591350:carba-1-(4-FBzlGly7)dOT; D010121:Oxytocin