OBJECTIVEThe immediate effects of oxytocin on myometrial signal transduction have been described. However, the longer term effects (up to an hour) on the myometrial proteome have not. We combined in vitro contractility with proteomic analysis to determine the protein changes associated with oxytocin-induced myometrial activity.STUDY DESIGNHuman myometrial biopsies were taken at elective caesarean section prior to administration of oxytocics. Strips were mounted in an organ bath and exposed to oxytocin (10(-8) mol/L), the oxytocin antagonist L372,662 (10(-7) mol/L), or vehicle (n = 5 for each) for 60 minutes. Contractility was determined and expressed as a percentage of pretreatment for each strip. At the end of the contractility experiment, proteins were extracted and separated by two-dimensional (2D) gel electrophoresis. Two-dimensional gels were analyzed by PDQuest and proteins of interest identified by mass spectrometry.RESULTSIdentified proteins that demonstrated differences as a result of treatment with oxytocin or the oxytocin receptor antagonist L372,662 were Annexin-A3, Osteoglycin, HSP70-protein 2, 2 isoforms of Cytokeratin 19, Desmin, EHD2, Protein disulfide isomerase A3, BIGH3, transgelin, thioredoxin reductase, triose phosphate isomerase, pyruvate kinase, elongation factor 1gamma, and alpha-Actin-3. These proteins can be grouped into 5 classes of protein, those associated with cytoskeletal function, contractile/oxidative stress, protein synthesis, extracellular matrix proteins, and energy metabolism.CONCLUSIONThis study demonstrates that oxytocin has longer term (1 hour) effects on the myometrial proteome.

01 Jun 1998·Journal of Medicinal ChemistryQ1 · MEDICINE

Development of Orally Active Oxytocin Antagonists: Studies on 1-(1-{4-[1-(2-Methyl-1-oxidopyridin-3-ylmethyl)piperidin-4-yloxy]-2- methoxybenzoyl}piperidin-4-yl)-1,4-dihydrobenz[d][1,3]oxazin-2-one (L-372,662) and Related Pyridines

Q1 · MEDICINE

Article

Author: Kuo, Michelle S. ; Freidinger, Roger M. ; Halpin, Rita A. ; Michelson, Stuart R. ; Guare, James P. ; Bell, Ian M. ; Gallicchio, Steven N. ; Hobbs, Doug W. ; Guidotti, Maribeth T. ; Reiss, Duane R. ; Mathre, David J. ; Williams, Peter D. ; Pettibone, Douglas J. ; Lis, Edward V. ; Woyden, Carla J. ; Homnick, Carl F. ; Erb, Jill M. ; Vickers, Stanley ; Pawluczyk, Joseph M.

The previously reported oxytocin antagonist L-371,257 (2) has been modified at its acetylpiperidine terminus to incorporate various pyridine N-oxide groups. This modification has led to the identification of compounds with improved pharmacokinetics and excellent oral bioavailability. The pyridine N-oxide series is exemplified by L-372,662 (30), which possessed good potency in vitro (Ki = 4.1 nM, cloned human oxytocin receptor) and in vivo (intravenous AD50 = 0.71 mg/kg in the rat), excellent oral bioavailability (90% in the rat, 96% in the dog), good aqueous solubility (>8.5 mg/mL at pH 5.2) which should facilitate formulation for iv administration, and excellent selectivity against the human arginine vasopressin receptors. Incorporation of a 5-fluoro substituent on the central benzoyl ring of this class of oxytocin antagonists enhanced in vitro and in vivo potency but was detrimental to the pharmacokinetic profiles of these compounds. Although lipophilic substitution around the pyridine ring of compound 30 gave higher affinity in vitro, such substituents were a metabolic liability and caused shortfalls in vivo. Two approaches to prevent this metabolism, addition of a cyclic constraint and incorporation of trifluoromethyl groups, were examined. The former approach was ineffective because of metabolic hydroxylation on the constrained ring system, whereas the latter showed improvement in plasma pharmacokinetics in some cases.

01 Jan 1998·Advances in Experimental Medicine and BiologyQ4 · MEDICINE

Progress in the Development of Oxytocin Antagonists for Use in Preterm Labor

Q4 · MEDICINE

Article

Author: Peter D. Williams ; Mark G. Bock ; Douglas J. Pettibone ; Ben E. Evans ; Roger M. Freidinger

There is currently a need for new therapeutic agents for treating preterm labor which could offer improved safety and efficacy beyond what has been achieved with the widely employed beta-mimetics. In this regard, the longstanding hypothesis of oxytocin receptor blockade as representing a potentially more selective method of tocolysis has continued to gain support from results obtained in clinical studies with the peptide oxytocin antagonist, atosiban. Our laboratory has focussed on the identification of non-peptide oxytocin antagonists with properties suitable for both oral and intravenous administration. We have previously described the development of potent, camphor-based oxytocin antagonists, including L-368,899 which entered phase I human studies. More recently we have pursued a new structural class of oxytocin antagonists based on the 1-(N-benzoylpiperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one template. L-372,662 is a new member of this structural class and in our preclinical assays possesses an attractive overall profile from the standpoint of human oxytocin receptor affinity (Ki = 4.9 nM), human oxytocin vs. vasopressin receptor selectivity (> 500-fold), potency as an antagonist of oxytocin-induced uterine contractions in late gestation pregnant rhesus monkeys (AD50 = 36 micrograms/kg), oral bioavailability (F = 90% in dogs), and aqueous solubility (10 mg/mL).

100 Deals associated with L-372662

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Indication	Highest Phase	Country/Location	Organization	Date
Obstetric Labor, Premature	Discovery	US	Merck & Co., Inc.	-

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