Second Generation “Peptoid” CCK-B Receptor Antagonists:  Identification and Development ofN-(Adamantyloxycarbonyl)-α-methyl-(R)-tryptophan Derivative (CI-1015) with an Improved Pharmacokinetic Profile

Abstract

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. This SAR study led to the identification of tricyclo[3.3.1.1(3,7)]dec-2-yl [1S-[1 alpha(S*)2 beta]-[2-[(2-hydroxycyclohexyl)amino]-1-(1H-indol-3- ylmethyl)-1-methyl-2-oxoethyl]carbamate (CI-1015, 31) with binding affinities of 3.0 and 2900 nM for the CCK-B and CCK-A receptors, respectively. The compound showed CCK-B antagonist profile in the rat ventromedial hypothalamus assay with a Ke of 34 nM. It also showed an anxiolytic like profile orally in a standard anxiety paradigm (X-maze) with a minimum effective dose (MED) of 0.1 microgram/kg. Although the compound is less water soluble than CI-988, oral bioavailability in rat was improved nearly 10 times relative to CI-988 when dosed in HP beta CD. The blood-brain permeability of CI-1015 (31) was also enhanced relative to CI-988 (5). On the basis of the overall improved pharmacokinetic profile as well as enhanced brain penetration, CI-1015 (31) was chosen as a development candidate.

The Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives

“…Due to problems with the oral bioavailability of some of the peptoids reported hitherto, smaller compounds were sought as CCK-B antagonists. 557 Notably, the 2-Adoc-αMe-Trp motif was maintained in these compounds. Structure 266 displayed favorable selectivity (K i (CCK-B) = 3.0 nM; K i (CCK-A) = 2,900 nM), improved oral bioavailability in rats as well as better penetration of the BBB.…”

Therapeutic and chemical developments of cholecystokinin receptor ligands

“…Among the most potent drugs, CI-988 (Figure 5, 21) was the first compound described [92]. Structural modifications led to compounds like CI-1015 (22) [93] and RB 211 (Figure 5, 23) [94] which have an improved bioavailability and stability toward enzymatic and acidic degradation. Ureiodoacetamide derivatives represent another important dipeptoid series based on a glycine-glycine linkage.…”

Tyrosine 220 in the 5th Transmembrane Domain of the Neuromedin B Receptor Is Critical for the High Selectivity of the Peptoid Antagonist PD168368

“…These peptoids may act as either agonists or antagonists at neuropeptide receptors. To date, several classes of peptoid antagonists for receptors of gastrointestinal (GI) 1 hormones/neurotransmitters have been described including for cholecystokinin (3)(4)(5), somatostatin (6), tachykinins (7)(8)(9), or bombesin (10) receptors. They have been proven useful in helping to examine the role of these receptors in mediating various physiological and pathophysiological processes and they may be useful as therapeutic agents in such conditions as panic attacks (1,2,5).…”