Burnette Barry L, Selness Shaun, Devraj Raj, Jungbluth Gail, Kurumbail Ravi, Stillwell Loreen, Anderson Gary, Mnich Stephen, Hirsch Jeffrey, Compton Robert, De Ciechi Pamela, Hope Heidi, Hepperle Michael, Keith Robert H, Naing Win, Shieh Huey, Portanova Joseph, Zhang Yan, Zhang Jian, Leimgruber Richard M, Monahan Joseph
Pfizer Global Research and Development, Pfizer, Chesterfield, Mo. 63017, USA.
Pharmacology. 2009;84(1):42-60. doi: 10.1159/000227286. Epub 2009 Jul 4.
SD0006 is a diarylpyrazole that was prepared as an inhibitor of p38 kinase-alpha (p38alpha). In vitro, SD0006 was selective for p38alpha kinase over 50 other kinases screened (including p38gamma and p38delta with modest selectivity over p38beta). Crystal structures with p38alpha show binding at the ATP site with additional residue interactions outside the ATP pocket unique to p38alpha that can confer advantages over other ATP competitive inhibitors. Direct correlation between inhibition of p38alpha activity and that of lipopolysaccharide-stimulated TNFalpha release was established in cellular models and in vivo, including a phase 1 clinical trial. Potency (IC(50)) for inhibiting tumor necrosis factor-alpha (TNFalpha) release, in vitro and in vivo, was <200 nmol/l. In vivo, SD0006 was effective in the rat streptococcal-cell-wall-induced arthritis model, with dramatic protective effects on paw joint integrity and bone density as shown by radiographic analysis. In the murine collagen-induced arthritis model, equivalence was demonstrated to anti-TNFalpha treatment. SD0006 also demonstrated good oral anti-inflammatory efficacy with excellent cross-species correlation between the rat, cynomolgus monkey, and human. SD0006 suppressed expression of multiple proinflammatory proteins at both the transcriptional and translational levels. These properties suggest SD0006 could provide broader therapeutic efficacy than cytokine-targeted monotherapeutics.
SD0006是一种二芳基吡唑，被制备用作p38激酶α（p38α）的抑制剂。在体外，与筛选的其他50多种激酶相比，SD0006对p38α激酶具有选择性（包括对p38γ和p38δ有一定选择性，对p38β的选择性适中）。与p38α的晶体结构显示其在ATP位点结合，在ATP口袋外还有独特的额外残基相互作用，这是p38α所特有的，可能赋予其相对于其他ATP竞争性抑制剂的优势。在细胞模型和体内，包括一项1期临床试验中，建立了p38α活性抑制与脂多糖刺激的TNFα释放抑制之间的直接相关性。在体外和体内，抑制肿瘤坏死因子α（TNFα）释放的效力（IC50）<200 nmol/l。在体内，SD0006在大鼠链球菌细胞壁诱导的关节炎模型中有效，X线分析显示对 paw关节完整性和骨密度有显著保护作用。在小鼠胶原诱导的关节炎模型中，证明其与抗TNFα治疗等效。SD0006还显示出良好的口服抗炎疗效，在大鼠、食蟹猴和人类之间具有出色的跨物种相关性。SD0006在转录和翻译水平上均抑制多种促炎蛋白的表达。这些特性表明SD0006可能比细胞因子靶向单药治疗提供更广泛的治疗效果。
