Hu Essa, Andrews Kristin, Chmait Samer, Zhao Xiaoning, Davis Carl, Miller Silke, Hill Della Puppa Geraldine, Dovlatyan Mary, Chen Hang, Lester-Zeiner Dianna, Able Jessica, Biorn Christopher, Ma Ji, Shi Jianxia, Treanor James, Allen Jennifer R
Department of Medicinal Chemistry, Department of Molecular Structure, Department of Pharmacokinetics and Drug Metabolism, and Department of Neuroscience, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 93012-1799, United States.
Department of Molecular Structure and Characterization, Department of Neuroscience, and Department of Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
ACS Med Chem Lett. 2014 Mar 28;5(6):700-5. doi: 10.1021/ml5000993. eCollection 2014 Jun 12.
We report the discovery of novel imidazo[4,5-b]pyridines as potent and selective inhibitors of PDE10A. The investigation began with our recently disclosed ketobenzimidazole 1, which exhibited single digit nanomolar PDE10A activity but poor oral bioavailability. To improve oral bioavailability, we turned to novel scaffold imidazo[4,5-b]pyridine 2, which not only retained nanomolar PDE10A activity but was also devoid of the morpholine metabolic liability. Structure-activity relationship studies were conducted systematically to examine how various regions of the molecule impacted potency. X-ray cocrystal structures of compounds 7 and 24 in human PDE10A helped to elucidate the key bonding interactions. Five of the most potent and structurally diverse imidazo[4,5-b]pyridines (4, 7, 12b, 24a, and 24b) with PDE10A IC50 values ranging from 0.8 to 6.7 nM were advanced into receptor occupancy studies. Four of them (4, 12b, 24a, and 24b) achieved 55-74% RO at 10 mg/kg po.
我们报告了新型咪唑并[4,5-b]吡啶作为磷酸二酯酶10A（PDE10A）强效和选择性抑制剂的发现。研究始于我们最近公开的酮苯并咪唑1，其表现出个位数纳摩尔的PDE10A活性，但口服生物利用度较差。为了提高口服生物利用度，我们转向新型骨架咪唑并[4,5-b]吡啶2，它不仅保留了纳摩尔的PDE10A活性，而且没有吗啉代谢负担。系统地进行了构效关系研究，以考察分子的各个区域如何影响活性。人PDE10A中化合物7和24的X射线共晶体结构有助于阐明关键的键合相互作用。五种具有最强大和结构多样性的咪唑并[4,5-b]吡啶（4、7、12b、24a和24b），其PDE10A IC50值在0.8至6.7 nM之间，进入受体占有率研究。其中四种（4、12b、24a和24b）在10 mg/kg口服给药时实现了55-74%的受体占有率。
