Lau Jesper, Behrens Carsten, Sidelmann Ulla G, Knudsen Lotte B, Lundt Behrend, Sams Christian, Ynddal Lars, Brand Christian L, Pridal Lone, Ling Anthony, Kiel Dan, Plewe Michael, Shi Shengua, Madsen Peter
Protein Engineering, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
J Med Chem. 2007 Jan 11;50(1):113-28. doi: 10.1021/jm058026u.
A weak human glucagon receptor antagonist with an IC50 of 7 microM was initially found by screening of libraries originally targeted to mimic the binding of the glucagon-like peptide (GLP-1) hormone to its receptor. Optimization of this hit for binding affinity for the glucagon receptor led to ligands with affinity in the nanomolar range. In addition to receptor binding, optimization efforts were made to stabilize the molecules against fast metabolic turnover. A potent antagonist of the human human glucagon receptor was obtained that had 17% oral availability in rats with a plasma half-life of 90 min. The major metabolites of this lead were identified and used to further optimize this series with respect to pharmacokinetic properties. This final optimization led to a potent glucagon antagonist that was orally available in rats and dogs and was efficacious in lowering blood glucose levels in a diabetic animal model.
最初通过筛选最初旨在模拟胰高血糖素样肽（GLP-1）激素与其受体结合的文库，发现了一种IC50为7微摩尔的弱人胰高血糖素受体拮抗剂。对该命中物进行胰高血糖素受体结合亲和力优化，得到了纳摩尔范围内具有亲和力的配体。除了受体结合外，还进行了优化努力，以稳定分子以抵抗快速的代谢周转。获得了一种有效的人胰高血糖素受体拮抗剂，其在大鼠中的口服生物利用度为17%，血浆半衰期为90分钟。鉴定了该先导化合物的主要代谢物，并用于进一步优化该系列的药代动力学性质。这一最终优化产生了一种有效的胰高血糖素拮抗剂，其在大鼠和犬中口服可用，并且在糖尿病动物模型中能有效降低血糖水平。
