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 was written by Bell, Ian M.;Erb, Jill M.;Freidinger, Roger M.;Gallicchio, Steven N.;Guare, James P.;Guidotti, Maribeth T.;Halpin, Rita A.;Hobbs, Doug W.;Homnick, Carl F.;Kuo, Michelle S.;Lis, Edward V.;Mathre, David J.;Michelson, Stuart R.;Pawluczyk, Joseph M.;Pettibone, Douglas J.;Reiss, Duane R.;Vickers, Stanley;Williams, Peter D.;Woyden, Carla J.. And the article was included in Journal of Medicinal Chemistry in 1998.Related Products of 28478-46-8 This article mentions the following:
The previously reported oxytocin antagonist L-371,257 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 (I), which possessed good potency in vitro (Ki = 4.1 nM, cloned human oxytocin receptor) and in vivo (i.v. 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 i.v. 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 I 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. In the experiment, the researchers used many compounds, for example, Methyl 4-Hydroxy-2-methoxybenzoate (cas: 28478-46-8Related Products of 28478-46-8).
Methyl 4-Hydroxy-2-methoxybenzoate (cas: 28478-46-8) belongs to esters. Esters are widespread in nature and are widely used in industry. In nature, fats are in general triesters derived from glycerol and fatty acids. Esters are responsible for the aroma of many fruits. Liquid esters of low volatility serve as softening agents for resins and plastics. Esters also include many industrially important polymers. Polymethyl methacrylate is a glass substitute sold under the names Lucite and Plexiglas; polyethylene terephthalate is used as a film (Mylar) and as textile fibres sold as Terylene, Fortrel, and Dacron.Related Products of 28478-46-8
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