- Novel Gonadotropin-Releasing Hormone Antagonists: Peptides Incorporating Modified Nω-Cyanoguanidino Moieties
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In order to minimize the deleterious effects of histamine release resulting from the administration to rats and humans of some potent gonadotropin-releasing hormone (GnRH) antagonists, various arginine residues were replaced with the less basic Nω-cyano-Nω'-alkyl- or -arylhomoarginine, -arginine, or -p-aminophenylalanine and Nω-triazolyllysine, -ornithine or -p-aminophenylalanine residues in active analogues.These novel analogues were synthesized on a solid-phase support via a two-step modification of the Nω-NH2 of lysine, ornithine, or p-aminophenylalanineresidues in otherwise protected resin bound peptides.Most analogues were tested in the rat antiovulatory assay (AOA) and three in vitro assays: a pituitary cell culture assay, a binding assay to pituitary cell membranes, and a histamine release assay.Introduction of the cyanoguanidino and Nω-triazolyl moieties into GnRH analogues yielded several water-soluble antagonists which showed a desirable therapeutic ratio (low histamine release activity to high in vivo potency).Among them, "Azaline" (10, 1,DCpa2,DPal3,Lys5(atz),DLys6(atz),ILys8,DAla10>GnRH), inhibited ovulation in the rat by 90percent at 2 μg/rat with an ED50 in the in vitro histamine release assay comparable to that of GnRH itself.
- Theobald, Paula,Porter, John,Rivier, Catherine,Corrigan, Anne,Hook, William,et al.
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p. 2395 - 2402
(2007/10/02)
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- Synthesis of Bis(aryloxy)chloromethanes via Radical-Induced Chlorinations of Formaldehyde Diaryl Acetals
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Bis(aryloxy)chloromethanes 2 and bis(aryloxy)dichloromethanes 3 are prepared via radical-induced chlorinations of the formaldehyde diaryl acetals 1 with chlorine or sulfuryl chloride.
- Cambanis, Anton,Baeuml, Englbert,Mayr, Herbert
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- Diphenyl Cyanocarbonimidate. A Versatile Synthon for the Construction of Heterocyclic Systems
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A simple high yield synthesis of diphenyl cyanocarbonimidate is reported.This synthon may be used to prepare functionalized benzimidazoles, benzoxazoles and triazoles in good yield under mild conditions.
- Webb, R. Lee,Labaw, Clifford S.
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p. 1205 - 1206
(2007/10/02)
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