Charles F. Jewell

Absorption and disposition of a tripeptoid and a tetrapeptide in the rat

The present study is concerned with the absorption and disposition of a tripeptoid (N‐substituted glycine derivative) and a tetrapeptide in the rat. The two compounds have similar backbone structures but differ with respect to the presence or absence of peptide bond. [3H]tripeptoid and [3H]tetrapeptide were administered orally (30 mg kg−1) and intravenously (i.v.) (30 or 3 mg kg−1) to Sprague Dawley rats. Blood, urine and feces were collected at designated times for radioactivity and parent drug analysis. The intestinal absorptive clearances of the tripeptoid and tetrapeptide were studied using an in situ rat intestinal perfusion model. The octanol/water partition coefficient of these two compounds was also determined. The results showed that the peptoid and peptide have similar absorptive clearance and octanol/water partitioning, but different in vivo absorption and disposition characteristics. The absorptive clearances of the tripeptoid and tetrapeptide were 6.7 and 4.8×10−4 mL min−1 cm−1, respectively, and the corresponding octanol/water partition coefficients were 0.39 and 0.30. The extent of oral absorption of the tripeptoid was only 3–8%, consistent with its low absorptive clearance. In contrast, the apparent absorption of the tetrapeptide was >75% of the radioactive dose. The peptide was completely metabolized within 2 h after an i.v. dose, whereas the peptoid was stable in blood and was primarily eliminated in feces as intact drug. In conclusion, the difference in in vivo absorption and disposition between the peptoid and peptide was apparently due to the presence or absence of a peptide bond. The tetrapeptide was subject to rapid metabolism in the body. Its relatively high absorption appeared to represent the absorption of metabolized radioactive fragments. The peptoid appears to have advantages over the peptide in term of metabolic stability, but its low oral absorption and rapid biliary excretion present additional challenges in the selection of an optimal drug candidate. Copyright

Farnesyl chain modification of squalene synthase inhibitor benzylfarnesylamine: Conversion to the terminal bis(trifluoromethyl) derivative

Abstract Potent squalene synthase inhibitor 1 was converted to the bis(trifluoromethyl) analog 14 in 11% overall yield for 9 steps. The amine nitrogen of 1 was protected with the 2-(trimethylsilyl)ethoxycarbonyl (TEOC) protecting group. The 10,11 olefin was selectively epoxidized, cleaved and converted to the phosphonium salt 6. The ylid from 6 underwent a Wittig condensation with hexafluoroacetone to give the TEOC containing olefin 8. Tetrabutylammonium fluoride or HF could not remove the TEOC group without isomerizing the 10,11 olefin of the farnesyl chain to the E-9,10 olefin. The bis(trifluoromethyl) olefin of 8 is very sensitive to either acidic or basic conditions. However, it was found that BF3·Et2O could remove the TEOC group without the undesired isomerization to give 14.