Trivedi B K, Padia J K, Holmes A, Rose S, Wright D S, Hinton J P, Pritchard M C, Eden J M, Kneen C, Webdale L, Suman-Chauhan N, Boden P, Singh L, Field M J, Hill D
Department of Medicinal Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
J Med Chem. 1998 Jan 1;41(1):38-45. doi: 10.1021/jm970065l.
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.
我们之前描述了CI-988的设计与开发，它是CCK-4的类肽类似物，对CCK-B受体具有出色的结合亲和力和选择性。由于其在焦虑动物模型中具有抗焦虑特性，该化合物被开发为临床候选药物。然而，在其研发过程中发现，CI-988在啮齿类和非啮齿类动物中生物利用度都很低。在临床试验中进一步证实，CI-988的生物利用度较差。因此，需要鉴定一种具有改善药代动力学（PK）特征的类似物。其生物利用度差归因于吸收不良和肝脏有效摄取。我们设想降低母体化合物（5，MW = 614）的分子量会带来更好的吸收。因此，我们合成了一系列类似物，其中保持了受体结合所需的关键α-甲基色氨酸和金刚烷氧基羰基部分不变，而对C端进行了广泛修饰。这项构效关系（SAR）研究鉴定出三环[3.3.1.1(3,7)]癸-2-基 [1S-[1α(S*)2β]-[2-[(2-羟基环己基)氨基]-1-(1H-吲哚-3-基甲基)-1-甲基-2-氧代乙基]氨基甲酸酯（CI-1015，31），其对CCK-B和CCK-A受体的结合亲和力分别为3.0和2900 nM。该化合物在大鼠腹内侧下丘脑试验中显示出CCK-B拮抗剂特征，Ke为34 nM。在标准焦虑模型（X迷宫）中，它口服时也显示出抗焦虑样特征，最小有效剂量（MED）为0.1微克/千克。尽管该化合物的水溶性比CI-988低，但当以HPβCD给药时，大鼠口服生物利用度相对于CI-988提高了近10倍。相对于CI-988（5），CI-1015（31）的血脑通透性也有所增强。基于整体改善的药代动力学特征以及增强的脑渗透，CI-1015（31）被选为研发候选药物。
