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, NONPEPTIDE OXYTOCIN ANTAGONIST WITH POTENTIAL UTILITY FOR MANAGING PRETERM LABOR

• Published in: Journal of medicinal chemistry Vol. 37; no. 5; pp. 565 - 571
• Main Authors: WILLIAMS, PD, ANDERSON, PS, BALL, RG, BOCK, MG, CARROLL, L, CHIU, SHL, CLINESCHMIDT, BV, CULBERSON, JC, ERB, JM, EVANS, BE, FITZPATRICK, SL, FREIDINGER, RM, KAUFMAN, MJ, LUNDELL, GF, MURPHY, JS, PAWLUCZYK, JM, PERLOW, DS, PETTIBONE, DJ, PITZENBERGER, SM, THOMPSON, KL, VEBER, DF
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 04.03.1994
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; RECEPTOR; PARTURITION; CYCLIC HEXAPEPTIDE
• ISSN: 0022-2623
• DOI: 10.1021/jm00031a004

Modifications to the previously reported spiroindenylpiperidine camphorsulfonamide oxytocin (OT) antagonist L-366,509 have produced a new series of o-tolylpiperazine (TP) camphorsulfonamides. 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 V-1a, and V(2)ceptors. 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 (pA(2)=8.9) and in situ rat uterus (AD(50)=0.35 mg/kg after intravenous (iv) 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 iv dosing). On the basis of these favorable properties, 7 has begun clinical testing for use as an oral and iv tocolytic agent. Molecular modeling alignment studies have provided support for the hypothesis that the TP camphorsulfonamide portion of the non-peptide structures may serve as a mimetic of the important D-AA(2)-Ile(3) dipeptide (AA=aromatic amino acid) found in many potent OT antagonists from the cyclic hexapeptide and OT analogue structural classes.