Gingrich Diane E, Reddy Dandu R, Iqbal Mohamed A, Singh Jasbir, Aimone Lisa D, Angeles Thelma S, Albom Mark, Yang Shi, Ator Mark A, Meyer Sheryl L, Robinson Candy, Ruggeri Bruce A, Dionne Craig A, Vaught Jeffry L, Mallamo John P, Hudkins Robert L
Departments of Medicinal Chemistry, Cephalon, Inc, 145 Brandywine Parkway, West Chester, Pennsylvania 19380, USA.
J Med Chem. 2003 Dec 4;46(25):5375-88. doi: 10.1021/jm0301641.
A series of potent vascular endothelial growth factor R2 (VEGF-R2) tyrosine kinase inhibitors from a new indenopyrrolocarbazole template is reported. The structure-activity relationships for a series of 9-alkoxymethyl-12-(3-hydroxypropyl)indeno[2,1-a]pyrrolo[3,4-c]carbazole-5-ones revealed an optimal R9 substitution with ethoxymethyl 19 (VEGF-R2 IC(50) = 4 nM) and isopropoxymethyl 21 (VEGF-R2 IC(50) = 8 nM) being the most potent inhibitors in the series. The VEGF-R2 activity was reduced appreciably by increasing the size of the R9 alkoxy group or by alpha-methyl branching adjacent to the ring. The combined R9 alkoxymethyl and N12 hydroxypropyl substitutions were required for potent VEGF-R2 activity, and the corresponding thioether analogues were weaker than their ether counterparts. Compound 21 (R9 isopropoxymethyl, CEP-5214) was identified as a potent, low-nanomolar pan inhibitor of human VEGF-R tyrosine kinases, displaying IC(50) values of 16, 8, and 4 nM for VEGF-R1/FLT-1, VEGF-R2/KDR, and VEGF-R3/FLT-4, respectively, with cellular activity equivalent to the isolated enzyme activity. Compound 21 exhibited good selectivity against numerous tyrosine and serine/threonine kinases including PKC, Tie2, TrkA, CDK1, p38, JNK, and IRK. To increase water solubility and oral bioavailability, the N,N-dimethylglycine ester 40 was prepared. In pharmacokinetic studies in mice and rats, increased plasma levels of 21 were observed after oral administration of 40. Compound 21 demonstrated significant in vivo antitumor activity in numerous tumor models and was advanced into phase I clinical trials as the water-soluble N,N-dimethylglycine ester prodrug 40 (CEP-7055).
报道了一系列源自新型茚并吡咯并咔唑模板的强效血管内皮生长因子R2（VEGF-R2）酪氨酸激酶抑制剂。一系列9-烷氧基甲基-12-（3-羟丙基）茚并[2,1-a]吡咯并[3,4-c]咔唑-5-酮的构效关系表明，R9用乙氧基甲基19取代效果最佳（VEGF-R2 IC(50)=4 nM），异丙氧基甲基21（VEGF-R2 IC(50)=8 nM）是该系列中最有效的抑制剂。增大R9烷氧基的尺寸或在环附近引入α-甲基支链会明显降低VEGF-R2活性。强效VEGF-R2活性需要R9烷氧基甲基和N12羟丙基取代相结合，相应的硫醚类似物比其醚类似物活性弱。化合物21（R9为异丙氧基甲基，CEP-5214）被鉴定为一种强效的低纳摩尔浓度的人VEGF-R酪氨酸激酶泛抑制剂，对VEGF-R1/FLT-1、VEGF-R2/KDR和VEGF-R3/FLT-4的IC(50)值分别为16 nM、8 nM和4 nM，其细胞活性与分离的酶活性相当。化合物21对包括PKC、Tie2、TrkA、CDK1、p38、JNK和IRK在内的多种酪氨酸和丝氨酸/苏氨酸激酶具有良好的选择性。为了提高水溶性和口服生物利用度，制备了N,N-二甲基甘氨酸酯40。在小鼠和大鼠的药代动力学研究中，口服40后观察到21的血浆水平升高。化合物21在多种肿瘤模型中显示出显著的体内抗肿瘤活性，并作为水溶性N,N-二甲基甘氨酸酯前药40（CEP-7055）进入I期临床试验。
