Author: Bock, Mark G. ; Williams, Peter D. ; Tung, Roger D. ; Perlow, Debra S. ; Garsky, Victor M. ; Whitter, Willie L. ; Gould, Norman P. ; Lundell, G. F. ; Erb, Jill M.

A new structural class of cyclic hexapeptide oxytocin antagonists derived from Streptomyces silvensis and typified by L-365,209 (cyclo-[L-prolyl1-D-phenylalanyl2-L- isoleucyl3-D-dehydropiperazyl4-L-dehydroperazyl5-D-(N- methyl)phenylalanyl6]) was recently reported. In this paper we further delineate the structure-activity profile for this new class by systematic study of L-365,209 analogs obtained by total synthesis. The optimal combination of cyclic amino acid ring sizes at positions 1, 4, and 5 and the role of the N-alkyl substituent at position 6 was elucidated. The lipophilic amino acids at positions 2 and 3 and the unusual amino acid D-dehydropiperazic acid at position 4 were found to be the most critical residues for obtaining good oxytocin receptor affinity. Analogs containing a basic side chain at the less critical 5- and 6-positions maintained good receptor affinity and also had useful levels of water solubility for intravenous formulation. By combining potency- and solubility-enhancing substitutions, several analogs were identified that have the desired combination of properties in vitro (22, cyclo-[L-prolyl-D-tryptophanyl-L-isoleucyl-D-pipecolyl-L-pipeco lyl-D- histidyl]; 25, cyclo-[L-prolyl-D-2-naphthylalanyl-L-isoleucyl-D-pipecolyl-L -pipecolyl-D- histidyl]; 26, cyclo-[L-prolyl-D-tryptophanyl-L-isoleucyl-D-dehydropiperazyl-L-++ pipecolyl-D-histidyl]; 33, cyclo-[L-prolyl-D-tryptophanyl-L-isoleucyl-D-pipecolyl-L- piperazinylcarboxy-D-(N-methyl)phenylalanyl]; 34, cyclo-[L-prolyl-D-phenylalanyl-L-isoleucyl-D-dehydropiperazyl-L-or nithyl- D-(N-methyl)phenylalanyl]). In general, this class exhibited good selectivity for binding to the oxytocin receptor versus the arginine vasopressin V1a and V2 receptor subtypes, although increased V2 receptor affinity was observed in one case (32, cyclo[L-prolyl-D-2-naphthylalanyl-L-isoleucyl-D-pipecolyl-L- lysyl-D-(N- methyl)phenylalanyl]). Unexpectedly, compound 33 was found to stimulate contractions of the isolated rat uterus via activation of the uterine bradykinin receptor. Compounds 22, 25, 26, 33, and 34 were found to be potent antagonists of oxytocin-stimulated contraction of the rat uterus in vitro and in vivo. Compounds 22 and 25 were additionally characterized as potent antagonists of oxytocin-stimulated uterine contractions in the near-term pregnant rhesus monkey. These studies thus demonstrate the selectivity and efficacy of certain members of this novel class of antagonists and suggest their use as pharmacological tools in further defining the role of oxytocin in both term and preterm labor.

01 Jul 1990·Journal of Medicinal ChemistryQ1 · MEDICINE

Cyclic hexapeptide oxytocin antagonists. Potency-, selectivity-, and solubility-enhancing modifications

Q1 · MEDICINE

Article

Author: Pettibone, D. J. ; DiPardo, R. M. ; Clineschmidt, B. V. ; Williams, P. D. ; Garsky, V. M. ; Bock, M. G. ; Tung, R. D. ; Freidinger, Roger M. ; Erb, J. M.

Structural modifications of the novel cyclic hexapeptide oxytocin antagonist L-365,209 (I, Δ-Piz = dehydropiperazic acid) are reported.The analogs were prepared by total synthesis using either solution or solid-phase techniques.Acid lability of many intermediates required the use of N-fluorenylmethoxycarbonyl protection, and certain difficult couplings were accomplished with the new methodol. of AgCN catalysis of acid chloride acylations.High levels of oxytocin receptor affinity and selectivity can be achieved with substitutions at the 2- and 4-positions of I.Aqueous solubility can be increased substantially with the introduction of basic groups at the 5- and 6-positions.Several potent and selective oxytocin receptor ligands with sufficient solubility for i.v. administration have been identified.

01 Apr 1990·European Journal of Pharmacology: Molecular PharmacologyQ3 · MEDICINE

Identification of functional oxytocin receptors in lactating rat mammary gland in vitro

Q3 · MEDICINE

Article

Author: James A. Totaro ; Douglas J. Pettibone ; Carla J. Woyden

The oxytocin (OT) receptor of the lactating rat mammary gland was further characterized by radioligand binding and functional assays in vitro and compared to the uterine OT receptor. In equilibrium saturation binding studies, [3H]OT bound apparently to a single site in mammary tissue with an affinity (Kd = 0.98 nM) similar to that found in the uterus (Kd = 0.68 nM). Using a variety of ligands for OT and arginine vasopressin (AVP) receptors, binding studies indicated that the recognition profile of the mammary [3H]OT binding site closely resembled that found for the uterus but was distinct from the known AVP receptor subtypes. In functional studies, OT and the highly selective OT agonist, [Thr4,Gly7]OT, were potent activators of phosphatidylinositol (PI) turnover in both mammary and uterine slices (EC50 3-5 nM). L-365,209, a novel potent and selective OT antagonist, inhibited OT-stimulated PI turnover in both tissues with similar potencies. These data provide evidence that the high-affinity [3H]OT binding site found in rat mammary tissue during lactation is a functional OT receptor coupled to PI turnover.

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

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