2ND-GENERATION PEPTOID CCK-B RECEPTOR ANTAGONISTS - IDENTIFICATION AND DEVELOPMENT OF (ADAMANTYLOXYCARBONYL)-ALPHA-METHYL-(R)-TRYPTOPHAN DERIVATIVE (CI-1015) WITH AN IMPROVED PHARMACOKINETIC PROFILE

We have previously described the design and development of CI-988, a p eptoid analogue of CCK-4 with excellent binding affinity and selectivi ty for the CCK-B receptor. Due to its anxiolytic profile in animal mod els of anxiety, this compound was developed as a clinical candidate. H owever, during its development, it was determined that CI-988 had low bioavailability in both rodent and nonrodent species. In the clinic, i t was further established that CI-988 had poor bioavailability. Thus, there was a need to identify an analogue with an improved pharmacokine tic (PK) profile. The poor bioavailability was attributed to poor abso rption and efficient-hepatic extraction. We envisaged that reducing th e 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, req uired for receptor binding, were kept intact and the C-terminus was ex tensively modified. This SAR study led to the identification of tricyc lo[3.3.1.1(3,7)]dec-2-yl [1S-[1 alpha(S)2 1H-indol-3-ylmethyl)-1-meth yl-2-oxoethyl]carbamate (CI-1015, 31) with binding affinities of 3.0 a nd 2900 nM for the CCK-B and CCK-A receptors, respectively. The compou nd showed CCK-B antagonist profile in the rat ventromedial hypothalamu s assay with a K-e of 34 nM. It also showed an anxiolytic like profile orally in a standard anxiety paradigm (X-maze) with a minimum effecti ve dose (MED) of 0.1 mu g/kg. Although the compound is less water solu ble than CI-988, oral bioavailability in rat was improved nearly 10 ti mes relative to CI-988 when dosed in HP beta CD. The blood-brain perme ability of CI-1015 (31) was also enhanced relative to CI-988 (5). On t he basis of the overall improved pharmacokinetic profile as well as en hanced brain penetration, CI-1015 (31) was chosen as a development can didate.