Oxytocin clearance

Investigation of a related indole template, however, yielded potent compounds, as exemplified by the sulphonamide derivative (33). Activity was improved further by introducing steric constraints to the sidechain and introduction of a 7-methyl substituent on the indole ring, leading to compound (34) [82]. Derivatives generally possessed only moderate pharmacokinetic properties however (clearance 25-45 ml/min/kg in dog), which was attributed to metabolic vulnerability of the indole (C2-C3) double bond. Attempts to block metabolism by C2, C3 di-methyl substitution resulted in the loss of oxytocin activity. 

Kidney and liver. The kidney and the liver play the major role in the clearance of oxytocin and vasopressin from the circulation. Liver extracts inactivate oxytocin by a two-stage process. The first step consists in the reduction of the disulfide bond with the simultaneous oxidation of reduced gluthathione, the reductive cleavage of oxytocin being coupled to the oxidation of NADPH as follows ... 

However, compounds of the type 89 were reported to have low solubility and relatively high log D. This resulted in replacement of the 3,4-difluorobenzaldehyde with 2-methyloxazole-4-aldehyde in the U-4CR. Compound 92 (GSJC221149A) has been noted to have nanomolar affinity for the oxytocin receptor with > 1400-fold selectivity over the closely related vasopressin receptors. Compound 92 (Figure 7.3) has also shown to have a good rat pharmacokinetic profile and low human microsomal clearance and inhibits oxytocin-induced contraction in vivo in the anesthetized rat... 

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