Progress in the development of oxytocin antagonists for use in preterm labor.
From a targeted screening effort and medicinal chemistry program, L-368,899 was selected as the first orally-active oxytocin (OT) antagonist to enter clinical trials. In animal studies, L-368,899 was shown to be a potent and selective OT antagonist and was orally bioavailable in rats, dogs and chimpanzees. L-368,899 was further shown to be a potent OT antagonist in pregnant rhesus and to inhibit spontaneous nocturnal uterine contractions. In Phase I human studies, L-368,899 was generally well-tolerated given intravenously and showed significant plasma levels after oral administration. In addition, L-368,899 blocked OT-stimulated uterine activity in postpartum women with a potency similar to that in the pregnant rhesus monkey. More recently, another structural series has been pursued, represented by L-371,257 [1-(1-(4-(N-acetyl-4-piperidinyloxy)-2-methoxybenzoyl)pip eridin-4-yl)- 1,2-dihydro-4(H)-3,1-benzoxazin-2-one]. L-371,257 exhibits high affinity (Ki, 4.6 nM) for human uterine OT receptors with high selectivity vs. human vasopressin receptors. In rat tissues in vitro, L-371,257 is a potent and competitive OT antagonist (pA2, 8.4) and, in vivo, blocks OT-stimulated uterine activity given both i.v. and intraduodenally. L-371,257 highlights the promise of this novel structural class.
Pettibone
D J
DJ
Department of New Lead Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA.
Guidotti
M
M
Harrell
C M
CM
Jasper
J R
JR
Lis
E V
EV
O'Brien
J A
JA
Reiss
D R
DR
Woyden
C J
CJ
Bock
M G
MG
Evans
B E
BE
D000818:Animals; D048588:Benzoxazines; D001892:Camphanes / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D004285:Dogs; D005260:Female; D006727:Hormone Antagonists / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D066298:In Vitro Techniques; D008253:Macaca mulatta; D015394:Molecular Structure; D007752:Obstetric Labor, Premature / Q000188:drug therapy* / Q000503:physiopathology; D010078:Oxazines / Q000737:chemistry / Q000627:therapeutic use; D010121:Oxytocin / Q000037:antagonists & inhibitors*; D002679:Pan troglodytes; D010879:Piperazines / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D010880:Piperidines / Q000737:chemistry / Q000627:therapeutic use; D011247:Pregnancy; D051381:Rats; D015149:Tocolytic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D014590:Uterine Contraction / Q000187:drug effects
D048588:Benzoxazines; D001892:Camphanes; D006727:Hormone Antagonists; C096766:L 371257; D010078:Oxazines; D010879:Piperazines; D010880:Piperidines; D015149:Tocolytic Agents; D010121:Oxytocin; C086206:L 368899