1-((7,7-Dimethyl-2(S)-(2(S)-amino-4-(methylsulfonyl)butyramido)bicyclo [2.2.1]-heptan-1(S)-yl)methyl)sulfonyl)-4-(2-methylphenyl)piperaz ine (L-368,899): an orally bioavailable, non-peptide oxytocin antagonist with potential utility for managing preterm labor.
Modifications to the previously reported spiroindenylpiperidine camphor-sulfonamide oxytocin (OT) antagonist L-366,509 have produced a new series of o-tolylpiperazine (TP) camphor-sulfonamides. A number of analogues in the TP series that incorporate a modified or unmodified L-methionine sulfone amide at the C2 endo position on the camphor ring exhibit high affinity for OT receptors (IC50 = 1.3-15 nM) and good selectivity for binding to OT versus arginine vasopressin V1a and V2 receptors. Several of these analogues were additionally characterized as potent antagonists of OT-stimulated contractions of the isolated and/or in situ rat uterus. Compound 7 (L-368,899) exhibited the best overall profile of OT receptor affinity (IC50 = 8.9 nM, rat uterus; 26 nM, human uterus), potency for inhibition of OT-stimulated contractions of the isolated rat uterus (pA2 = 8.9) and in situ rat uterus (AD50 = 0.35 mg/kg after intravenous (i.v.) administration and 7.0 mg/kg after intraduodenal administration), aqueous solubility (3.7 mg/mL at pH 5.0), and oral bioavailability in several species (35% (rat), 25% (dog), and 21% (chimpanzee) as estimated from radioreceptor determination of drug levels in plasma after oral and i.v. dosing). On the basis of these favorable properties, 7 has begun clinical testing for use as an oral and i.v. tocolytic agent. Molecular modeling alignment studies have provided support for the hypothesis that the TP camphor-sulfonamide portion of the non-peptide structures may serve as a mimetic of the important D-AA2-Ile3 dipeptide (AA = aromatic amino acid) found in many potent OT antagonists from the cyclic hexapeptide and OT analogue structural classes.
Williams
P D
PD
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486.
Anderson
P S
PS
Ball
R G
RG
Bock
M G
MG
Carroll
L
L
Chiu
S H
SH
Clineschmidt
B V
BV
Culberson
J C
JC
Erb
J M
JM
Evans
B E
BE
D000818:Animals; D001682:Biological Availability; D001892:Camphanes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004285:Dogs; D005260:Female; D006801:Humans; D008253:Macaca mulatta; D008958:Models, Molecular; D015394:Molecular Structure; D007752:Obstetric Labor, Premature / Q000188:drug therapy*; D010121:Oxytocin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010879:Piperazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D018045:Receptors, Oxytocin / Q000378:metabolism; D013329:Structure-Activity Relationship; D015149:Tocolytic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D014590:Uterine Contraction / Q000187:drug effects
D001892:Camphanes; D010879:Piperazines; D018045:Receptors, Oxytocin; D015149:Tocolytic Agents; D010121:Oxytocin; C086206:L 368899