Inhibition of vascular endothelial growth factor-A (VEGF) signaling is a promising therapeutic approach that aims to stabilize the progression of solid malignancies by abrogating tumor-induced angiogenesis. This may be accomplished by inhibiting the kinase activity of VEGF receptor-2 (KDR), which has a key role in mediating VEGF-induced responses. The novel indole-ether quinazoline AZD2171 is a highly potent (IC50 < 1 nmol/L) ATP-competitive inhibitor of recombinant KDR tyrosine kinase in vitro. Concordant with this activity, in human umbilical vein endothelial cells, AZD2171 inhibited VEGF-stimulated proliferation and KDR phosphorylation with IC50 values of 0.4 and 0.5 nmol/L, respectively. In a fibroblast/endothelial cell coculture model of vessel sprouting, AZD2171 also reduced vessel area, length, and branching at subnanomolar concentrations. Once-daily oral administration of AZD2171 ablated experimental (VEGF-induced) angiogenesis in vivo and inhibited endochondral ossification in bone or corpora luteal development in ovary; physiologic processes that are highly dependent upon neovascularization. The growth of established human tumor xenografts (colon, lung, prostate, breast, and ovary) in athymic mice was inhibited dose-dependently by AZD2171, with chronic administration of 1.5 mg per kg per day producing statistically significant inhibition in all models. A histologic analysis of Calu-6 lung tumors treated with AZD2171 revealed a reduction in microvessel density within 52 hours that became progressively greater with the duration of treatment. These changes are indicative of vascular regression within tumors. Collectively, the data obtained with AZD2171 are consistent with potent inhibition of VEGF signaling, angiogenesis, neovascular survival, and tumor growth. AZD2171 is being developed clinically as a once-daily oral therapy for the treatment of cancer.
A series of substituted 4-anilinoquinazolines and related compounds were synthesized as potential inhibitors of vascular endothelial growth factor (VEGF) receptor (Flt and KDR) tyrosine kinase activity. Enzyme screening indicated that a narrow structure-activity relationship (SAR) existed for the bicyclic ring system, with quinazolines, quinolines, and cinnolines having activity and with quinazolines and quinolines generally being preferred. Substitution of the aniline was investigated and clearly indicated that small lipophilic substituents such as halogens or methyl were preferred at the C-4' position. Small substituents such as hydrogen and fluorine are preferred at the C-2' position. Introduction of a hydroxyl group at the meta position of the aniline produced the most potent inhibitors of Flt and KDR tyrosine kinases activity with IC(50) values in the nanomolar range (e.g. 10, 12, 13, 16, and 18). Investigation of the quinazoline C-6 and C-7 positions indicates that a large range of substituents are tolerated at C-7, whereas variation at the C-6 is more restricted. At C-7, neutral, basic, and heteroaromatic side chains led to very potent compounds, as illustrated by the methoxyethoxy derivative 13 (IC(50) < 2 nM). Our inhibitors proved to be very selective inhibitors of Flt and KDR tyrosine kinase activity when compared to that associated with the FGF receptor (50- to 3800-fold). Observed enzyme profiles translated well with respect to potency and selectivity for inhibition of growth factor stimulated proliferation of human umbilical vein endothelial cells (HUVECs). Oral administration of selected compounds to mice produced total plasma levels 6 h after dosing of between 3 and 49 microM. In vivo efficacy was demonstrated in a rat uterine oedema assay where significant activity was achieved at 60 mg/kg with the meta hydroxy anilinoquinazoline 10. Inhibition of growth of human tumors in athymic mice has also been demonstrated: compound 34 inhibited the growth of established Calu-6 lung carcinoma xenograft by 75% (P < 0.001, one tailed t-test) following daily oral administration of 100 mg/kg for 21 days.
We have previously shown that 4-anilinoquinazolines can be potent inhibitors of vascular endothelial growth factor (VEGF) receptor (Flt-1 and KDR) tyrosine kinase activity. A novel subseries of 4-anilinoquinazolines that possess basic side chains at the C-7 position of the quinazoline nucleus have been synthesized. This subseries contains potent, nanomolar inhibitors of KDR (median IC(50) 0.02 microM, range 0.001-0.04 microM), which are comparatively less potent vs Flt-1 tyrosine kinase (median IC(50) 0.55 microM, range 0.02-1.6 microM). The compounds also retain some inhibitory activity against the tyrosine kinase associated to the endothelial growth factor receptor (EGFR) (median IC(50) 0.2 microM, range 0.075-0.8 microM) but demonstrate selectivity vs that associated to the FGF receptor 1 (median IC(50) 2.5 microM, range 0.9-19 microM). This selectivity profile is also evident in a growth factor-stimulated human endothelial cell (HUVEC) proliferation assay (i.e., inhibition of VEGF > EGF > FGF), with inhibition of VEGF-induced proliferation being achieved at nanomolar concentrations (median IC(50) 0.06 microM). Further examination of compound 2 (ZD6474) in recombinant enzyme assays revealed excellent selectivity for the inhibition of KDR tyrosine kinase (IC(50) 0.04 microM) vs the kinase activity of erbB2, MEK, CDK-2, Tie-2, IGFR-1R, PDK, PDGFRbeta, and AKT (IC(50) range: 1.1 to >100 microM). Anilinoquinazolines possessing basic C-7 side chains exhibited markedly improved aqueous solubility over previously described anilinoquinazolines possessing neutral C-7 side chains (up to 500-fold improvement at pH 7.4). In addition, aqueous solubility of the neutral fraction present at pH 7.4 of the basic subseries of anilinoquinazoline proved to be higher than that of the neutral analogue 1 (ZD4190). Oral administration of representative compounds to mice (50 mg/kg) produced plasma levels between 0.2 and 3 microM at 24 h after dosing. Our development candidate 2 demonstrated a very attractive in vitro profile combined with excellent solubility (330 microM at pH 7.4) and good oral bioavailability in rat and dog (> 80 and > 50%, respectively). This compound demonstrated highly significant, dose-dependent, antitumor activity in athymic mice. Once daily oral administration of 100 mg/kg of compound 2 for 21 days inhibited the growth of established Calu-6 lung carcinoma xenografts by 79% (P < 0.001, Mann Whitney rank sum test), and substantial inhibition (36%, P < 0.02) was evident with 12.5 mg/kg/day.
Arimidex is a potent and selective aromatase inhibitor undergoing evaluation as a treatment for postmenopausal women with advanced breast cancer. Studies to determine the pharmacology of Arimidex were conducted in both animals and humans. In animals, Arimidex was selective for the aromatase enzyme, elicited maximal activity at about 0.1 mg/kg, did not interfere with steroid hormones produced by the adrenal glands, and, at a dose of 1 mg/kg, had no detectable pharmacologic activity other than aromatase inhibition. Absorption of ZD1033, the active component of Arimidex, was rapid and virtually complete after oral administration to animals. ZD1033 was extensively metabolized in animals after oral administration; the metabolites were excreted predominantly in urine. The pharmacodynamic, pharmacokinetic, and safety profiles of single and multiple daily doses of Arimidex were determined in humans. Doses of 1 to 10 mg of Arimidex suppressed estradiol to the maximum degree measurable. Arimidex had no clinically significant effects on key enzymes that regulate cortisol and aldosterone biosynthesis. Absorption of ZD1033 was rapid, with maximum plasma concentrations occurring within 2 hours after oral administration. Plasma concentrations of ZD1033 rose with increasing doses of Arimidex. The elimination half-life of ZD1033 in humans ranged from 30 to 60 hours. Urinary excretion accounted for a small percentage of each dose. A 3- to 4-fold accumulation of ZD1033 in plasma occurred after daily administration of 3-, 5-, or 10-mg doses. Arimidex was well tolerated. Phase III studies are under way to determine the efficacy and safety of Arimidex in postmenopausal women with advanced breast cancer.
ZM 189,154 ([1RS,2RS]-2-(4-hydroxyphenyl)-2-methyl- 1-[9-(4,4,5,5,5-penta-fluoropentyl)sulphinylnonyl]-1,2,3,4- tetrahydronaphth-6-ol) is a non-steroidal pure antioestrogen. It has a high relative affinity for the oestrogen receptor, completely blocks the trophic action of oestradiol (OE2) on the uterus in immature and ovariectomized (OVX) adult rats and, in the latter, also completely blocks the trophic action of OE2 on vagina, bone and growth rate. ZM 189,154 displays no intrinsic oestrogen-agonist activity on uterus, vagina, bone, LH secretion or growth rate in OVX rats. Differential sensitivity of OE2-regulated processes was more apparent in intact rats. Daily doses of 0.6 mg/kg per day of ZM 189,154 blocked ovulation; 2 mg/kg per day achieved maximal uterine atrophy but did not affect bone density or growth rate; 10 mg/kg per day produced a broader spectrum of effects (reduced bone density, increased basal LH, slightly increased growth rate), but the magnitude of these was smaller than after ovariectomy; the 10 mg/kg dose also produced multiple ovarian follicular cysts. The failure of ZM 189,154 to achieve complete ovariectomy-like effects in intact rats may be due to the action of ovarian factors other than OE2, or to the circulating OE2 levels resulting from the disturbance to ovarian function posing too strong a challenge to the antagonist.
ICI 182,780 is a potent specific pure antioestrogen which may offer advantages in breast cancer treatment compared with partial agonists like tamoxifen. To characterize further the potency and efficacy of ICI 182,780, its effects on the uterus of ovariectomized, oestrogen-treated monkeys (Macaca nemestrina) have been measured using magnetic resonance imaging (MRI). Quantitative MRI allows accurate non-invasive repetitive measurements of endometrial and myometrial volume following hormonal treatments, using each animal as its own control. Single i.m. injections of a long-acting oil-based formulation of ICI 182,780 sustained blockade of oestradiol action on the monkey uterus in a dose-dependent manner for 3-6 weeks. Repeated injections of 4 mg ICI 182,780/kg at 4-weekly intervals provided increasingly effective blockade of uterine proliferation. In a short-acting formulation, ICI 182,780 also completely blocked the trophic action of oestradiol, administered concurrently, in ovariectomized monkeys. Similarly, ICI 182,780 caused involution of the uterus stimulated by prior treatment with oestradiol. The rate and extent of uterine involution in monkeys treated with ICI 182,780 was similar to that seen following oestrogen withdrawal. These studies demonstrate that ICI 182,780 is a fully effective pure antioestrogen in a primate.
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