Pfizer Global Research and Development, Groton Laboratories, Eastern Point Rd, Groton, Connecticut 06340, United States.
J Med Chem. 2011 Jun 23;54(12):4219-33. doi: 10.1021/jm200409s. Epub 2011 May 26.
Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-γ (PPARγ) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2a bound to the ligand binding domain of human PPARγ confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPARγ activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridine (2l) was identified as a potent angiotensin II type I receptor blocker (IC(50) = 1.6 nM) with partial PPARγ agonism (EC(50) = 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2l was demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2l was highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat.
从内部收集的血管紧张素 II 型 1 型受体拮抗剂中进行挖掘，以鉴定对过氧化物酶体增殖物激活受体 -γ（PPARγ）具有活性的化合物，发现了一系列新型咪唑并[4,5-b]吡啶 2 类化合物，它们对这两种受体均具有活性。先导化合物 2a 与人类 PPARγ 的配体结合域的晶体结构的早期可用性证实了该支架与核受体的相互作用方式，并有助于优化 PPARγ 活性。在新化合物中，（S）-3-（5-（2-（1H-四唑-5-基）苯基）-2,3-二氢-1H-茚-1-基）-2-乙基-5-异丁基-7-甲基-3H-咪唑并[4,5-b]吡啶（2l）被鉴定为具有强效血管紧张素 II 型 1 型受体阻断作用（IC（50）= 1.6 nM）和部分 PPARγ激动作用（EC（50）= 212 nM，最大 31%），且在大鼠体内具有口服生物利用度。2l 的双重药理学在高血压（SHR）和胰岛素抵抗（ZDF 大鼠）的动物模型中得到了证实。在 SHR 中，2l 非常有效地降低血压，而雄性 ZDF 大鼠的血糖和甘油三酯明显降低。
