Selecting an anti-malarial clinical candidate from two potent dihydroisoquinolones.
Selecting an anti-malarial clinical candidate from two potent dihydroisoquinolones.
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DOI：
10.1186/s12936-021-03617-1
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发表时间：
2021-02-19
期刊：
影响因子：
3
通讯作者：
Guy RK
中科院分区：
文献类型：
--
作者：
Chen Y;Zhu F;Hammill J;Holbrook G;Yang L;Freeman B;White KL;Shackleford DM;O'Loughlin KG;Charman SA;Mirsalis JC;Guy RK
正在进行的全球疟疾根除运动需要研发出高效、安全且具有成本效益的药物，这些药物要与现有的化疗药物无交叉耐药性。药物研发的一个关键步骤是从后期先导化合物中挑选出合适的临床候选药物。本文描述了根据两种强效二氢异喹啉酮（DHIQ）后期先导化合物SJ733和SJ311的理化性质、药代动力学（PK）以及毒性特征来挑选临床候选药物SJ733的过程。
对这些化合物进行了测试，以确定其理化性质，包括动力学和热力学溶解度、分配系数、渗透性、电离常数以及与血浆蛋白的结合。在来自小鼠、大鼠、狗和人类的微粒体和肝细胞中评估了代谢稳定性。使用重组人细胞色素酶评估了细胞色素P450抑制作用。在小鼠、大鼠和狗中研究了单次静脉注射或口服剂量的药代动力学特征。
尽管两种化合物显示出相似的理化性质，但SJ733在体外比SJ311具有更高的渗透性，但代谢稳定性较差。SJ733在小鼠、大鼠和狗中的单次剂量药代动力学研究表明其具有可观的口服生物利用度（60 - 100%），而SJ311的口服生物利用度较低（小鼠为23%，大鼠为40%）且肾清除率较高（在大鼠和狗中比SJ733高10 - 30倍），这表明其在人体内的暴露情况不太有利。SJ311还显示出较窄的剂量 - 比例暴露范围，在剂量高于200 mg/kg时血浆暴露趋于平稳。
基于更有利的剂量 - 比例暴露以及对向监管机构证明强大治疗指数能力的更强预期，SJ733被选为候选药物。
The ongoing global malaria eradication campaign requires development of potent, safe, and cost-effective drugs lacking cross-resistance with existing chemotherapies. One critical step in drug development is selecting a suitable clinical candidate from late leads. The process used to select the clinical candidate SJ733 from two potent dihydroisoquinolone (DHIQ) late leads, SJ733 and SJ311, based on their physicochemical, pharmacokinetic (PK), and toxicity profiles is described. The compounds were tested to define their physicochemical properties including kinetic and thermodynamic solubility, partition coefficient, permeability, ionization constant, and binding to plasma proteins. Metabolic stability was assessed in both microsomes and hepatocytes derived from mice, rats, dogs, and humans. Cytochrome P450 inhibition was assessed using recombinant human cytochrome enzymes. The pharmacokinetic profiles of single intravenous or oral doses were investigated in mice, rats, and dogs. Although both compounds displayed similar physicochemical properties, SJ733 was more permeable but metabolically less stable than SJ311 in vitro. Single dose PK studies of SJ733 in mice, rats, and dogs demonstrated appreciable oral bioavailability (60–100%), whereas SJ311 had lower oral bioavailability (mice 23%, rats 40%) and higher renal clearance (10–30 fold higher than SJ733 in rats and dogs), suggesting less favorable exposure in humans. SJ311 also displayed a narrower range of dose-proportional exposure, with plasma exposure flattening at doses above 200 mg/kg. SJ733 was chosen as the candidate based on a more favorable dose proportionality of exposure and stronger expectation of the ability to justify a strong therapeutic index to regulators.
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影响因子：
5.4
作者：
Long CA;Zavala F
通讯作者：
Zavala F
影响因子：
158.5
作者：
White, Nicholas J.;Pukrittayakamee, Sasithon;Leong, F. Joel
通讯作者：
Leong, F. Joel
DOI：
10.1073/pnas.1414221111
发表时间：
2014-12-16
影响因子：
11.1
作者：
Belen Jimenez-Diaz, Maria;Ebert, Daniel;Guy, R. Kiplin
通讯作者：
Guy, R. Kiplin
影响因子：
4.6
作者：
Goldgof GM;Durrant JD;Ottilie S;Vigil E;Allen KE;Gunawan F;Kostylev M;Henderson KA;Yang J;Schenken J;LaMonte GM;Manary MJ;Murao A;Nachon M;Murray R;Prescott M;McNamara CW;Slayman CW;Amaro RE;Suzuki Y;Winzeler EA
通讯作者：
Winzeler EA
DOI：
10.1056/nejmp1108322
发表时间：
2011-09-22
期刊：
The New England journal of medicine
影响因子：
--
作者：
Dondorp AM;Fairhurst RM;Slutsker L;Macarthur JR;Breman JG;Guerin PJ;Wellems TE;Ringwald P;Newman RD;Plowe CV
通讯作者：
Plowe CV