Oral bioavailability properties related

Extensive medicinal chemistry optimization of potency, selectivity pharmacokinetic, and pharmacodynamic properties finally led to potent, selective, and orally bioavailable GSK-221149A, which is synthesized as shown on Scheme 17 [35, 37, 38]. Peptidic oxytocin receptor antagonists are currently used to treat preterm labor, the main reason for infant death. The peptide derivatives by their nature are not orally bioavailable but must be administered i.v. Surprisingly, the peptide derivatives are less potent and less selective against several related receptors than GSK-221149A with half the molecular weight [39]. 

Structure-activity relations within chemical series have helped establish whether specific scaffolds and substitutions are an integral part of the Kvl.5 pharmacophore, or simply help display it. Frequently, property changes unrelated to Kvl.5 activity, such as unacceptable pharmacokinetic profiles, have prevented a thorough understanding of a particular pharmacophore. Other times, detailed pharmacophore characterization is compromised by a need to preserve or improve desirable properties in addition to Kvl.5 activity, such as oral bioavailability [43] or P-glycoprotein susceptibility, a predictor of reduced brain exposure [50]. 

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