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)piperazine (L-368,899): An Orally Bioavailable, Non-Peptide Oxytocin Antagonist with Potential Utility for Managing Preterm Labor
| Autor: | P D, Williams, P S, Anderson, R G, Ball, M G, Bock, L, Carroll, S H, Chiu, B V, Clineschmidt, J C, Culberson, J M, Erb, B E, Evans |
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| Rok vydání: | 1994 |
| Předmět: |
Models
Molecular Tocolytic agent Arginine Stereochemistry Biological Availability Crystallography X-Ray Oxytocin Piperazines Oxytocin Antagonist Sulfone Structure-Activity Relationship Uterine Contraction chemistry.chemical_compound Dogs Obstetric Labor Premature Pregnancy Drug Discovery medicine Animals Humans Camphanes Dipeptide Molecular Structure Chemistry Antagonist Macaca mulatta Rats Tocolytic Agents Receptors Oxytocin Molecular Medicine Female L-368 899 medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 37:565-571 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00031a004 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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