1.Second generation "peptoid" CCK-B receptor antagonists: identification and development of N-(adamantyloxycarbonyl)-alpha-methyl-(R)-tryptophan derivative (CI-1015) with an improved pharmacokinetic profile.
Trivedi BK1, Padia JK, Holmes A, Rose S, Wright DS, Hinton JP, Pritchard MC, Eden JM, Kneen C, Webdale L, Suman-Chauhan N, Boden P, Singh L, Field MJ, Hill D. J Med Chem. 1998 Jan 1;41(1):38-45.
We have previously described the design and development of CI-988, a peptoid analogue of CCK-4 with excellent binding affinity and selectivity for the CCK-B receptor. Due to its anxiolytic profile in animal models of anxiety, this compound was developed as a clinical candidate. However, during its development, it was determined that CI-988 had low bioavailability in both rodent and nonrodent species. In the clinic, it was further established that CI-988 had poor bioavailability. Thus, there was a need to identify an analogue with an improved pharmacokinetic (PK) profile. The poor bioavailability was attributed to poor absorption and efficient hepatic extraction. We envisaged that reducing the molecular weight of the parent compound (5, MW = 614) would lead to better absorption. Thus, we synthesized a series of analogues in which the key alpha-methyltryptophan and adamantyloxycarbonyl moieties, required for receptor binding, were kept intact and the C-terminus was extensively modified.
2.Malassezin--A novel agonist of the arylhydrocarbon receptor from the yeast Malassezia furfur.
Wille G1, Mayser P, Thoma W, Monsees T, Baumgart A, Schmitz HJ, Schrenk D, Polborn K, Steglich W. Bioorg Med Chem. 2001 Apr;9(4):955-60.
The yeast Malassezia furfur converts tryptophan into several indole compounds. One of these, malassezin, was identified as 2-(1H-indol-3-ylmethyl)-1H-indole-3-carbaldehyde (1). It was synthesized from N-Boc-indole-3-carbaldehyde in five steps with 12% overall yield. The compound easily cyclizes to indolo[3,2-b]carbazole (7) which is known to interact with the arylhydrocarbon receptor (AHR). Similarly, malassezin was found to induce cytochrome P450 as an agonist of AHR (EC50 = 1.57 microM) in rat hepatocytes.
