Kinesin spindle protein (KSP), an ATPase responsible for spindle pole separation during mitosis that is present only in proliferating cells, has become a novel and attractive anticancer target with ...potential for reduced side effects compared to currently available therapies. We report herein the discovery of the first known ATP-competitive inhibitors of KSP, which display a unique activity profile as compared to the known loop 5 (L5) allosteric KSP inhibitors that are currently under clinical evaluation. Optimization of this series led to the identification of biphenyl sulfamide 20, a potent KSP inhibitor with in vitro antiproliferative activity against human cells with either wild-type KSP (HCT116) or mutant KSP (HCT116 D130V). In a murine xenograft model with HCT116 D130V tumors, 20 showed significant antitumor activity following intraperitoneal dosing, providing in vivo proof-of-principle of the efficacy of an ATP-competitive KSP inhibitor versus tumors that are resistant to the other known KSP inhibitors.
A novel synthesis of 4H-pyrazolo-3,4-dpyrimidin-4-ones is described. This approach utilizes an in situ generated iminochloride as a key precursor for amidine formation, with subsequent base-catalyzed ...ring closure. This method represents a mild and efficient entry into this ring system which is amenable to diversification of the core template.
1
SB‐706375 potently inhibited 125IhU‐II binding to both mammalian recombinant and ‘native’ UT receptors (Ki 4.7±1.5 to 20.7±3.6 nM at rodent, feline and primate recombinant UT receptors and Ki ...5.4±0.4 nM at the endogenous UT receptor in SJRH30 cells).
2
Prior exposure to SB‐706375 (1 μM, 30 min) did not alter 125IhU‐II binding affinity or density in recombinant cells (KD 3.1±0.4 vs 5.8±0.9 nM and Bmax 3.1±1.0 vs 2.8±0.8 pmol mg−1) consistent with a reversible mode of action.
3
The novel, nonpeptidic radioligand 3HSB‐657510, a close analogue of SB‐706375, bound to the monkey UT receptor (KD 2.6±0.4 nM, Bmax 0.86±0.12 pmol mg−1) in a manner that was inhibited by both U‐II isopeptides and SB‐706375 (Ki 4.6±1.4 to 17.6±5.4 nM) consistent with the sulphonamides and native U‐II ligands sharing a common UT receptor binding domain.
4
SB‐706375 was a potent, competitive hU‐II antagonist across species with pKb 7.29–8.00 in HEK293‐UT receptor cells (inhibition of Ca2+i‐mobilization) and pKb 7.47 in rat isolated aorta (inhibition of contraction). SB‐706375 also reversed tone established in the rat aorta by prior exposure to hU‐II (Kapp∼20 nM).
5
SB‐706375 was a selective U‐II antagonist with 100‐fold selectivity for the human UT receptor compared to 86 distinct receptors, ion channels, enzymes, transporters and nuclear hormones (Ki/IC50>1 μM). Accordingly, the contractile responses induced in isolated aortae by KCl, phenylephrine, angiotensin II and endothelin‐1 were unaltered by SB‐706375 (1 μM).
6
In summary, SB‐706375 is a high‐affinity, surmountable, reversible and selective nonpeptide UT receptor antagonist with cross‐species activity that will assist in delineating the pathophysiological actions of U‐II in mammals.
British Journal of Pharmacology (2005) 145, 620–635. doi:10.1038/sj.bjp.0706229
Human urotensin‐II (hU‐II), a cyclic undecapeptide, is amongst the most potent mammalian vasoconstrictors identified, suggesting that hU‐II and its G‐protein‐coupled receptor (UT) may regulate ...cardiovascular homeostasis. Such a hypothesis would benefit greatly from the development of selective UT antagonists.
Although the somatostatin (SST) antagonist SB‐710411 (Cpa‐cD‐Cys‐Pal‐D‐Trp‐Lys‐Val‐Cys‐Cpa‐amide) is purported to block U‐II‐induced contractions in rat isolated aorta, little is known about its specific pharmacological properties.
SB‐710411 (10 μM) inhibited hU‐II‐induced contraction in rat isolated aorta causing a significant, parallel shift in the agonist concentration‐response curve (pKb 6.28±0.11; n=8) with no suppression of the Emax. In contrast, SB‐710411 did not alter the contractile actions of angiotensin‐II, phenylephrine, or KCl. Paradoxically, however, SB‐710411 potentiated the contractile response to endothelin‐1 (pEC50 8.02±0.16 and 8.54±0.11, P<0.01; n=8). Rather than being specific toSB‐710411, this phenomenon appears to be related to somatostatin receptor affinity and not intrinsic activity since the SST agonist somatostatin‐14 and antagonist cyclo‐somatostatin also potentiated endothelin‐1‐induced contraction.
SB‐710411 (10 μM) did not inhibit carbachol, sodium nitroprusside, IBMX, isoprenaline, and levcromakalim‐induced reversal of tone established with noradrenaline. In contrast, however, SB‐710411 significantly inhibited the reversal of tone established with endothelin‐1 using the same vasorelaxants.
In summary, although SB‐710411 inhibits the vasoconstrictor actions of hU‐II in a competitive, surmountable manner, it also possesses additional pharmacological actions. Thus, whilst the present study is amongst the first to detail the properties of a functional U‐II receptor antagonist, the data suggest caution be used when assessing data generated utilizing this moiety and other SST analogues.
British Journal of Pharmacology (2002) 137, 449–458. doi:10.1038/sj.bjp.0704887
SAR exploration of the central diamine, benzyl, and terminal aminoalkoxy regions of the N-cyclic azaalkyl benzamide series led to the identification of very potent human urotensin-II receptor ...antagonists such as 1a with a
K
i of 4
nM. The synthesis and structure–activity relationships (SAR) of N-cyclic azaalkyl benzamides are described.
SAR exploration of the central diamine, benzyl, and terminal aminoalkoxy regions of the N-cyclic azaalkyl benzamide series led to the identification of very potent human urotensin-II receptor antagonists such as
1a with a
K
i of 4
nM. The synthesis and structure–activity relationships (SAR) of N-cyclic azaalkyl benzamides are described.
High throughput screening of the corporate compound collection led to the discovery of a novel series of substituted aminoalkoxybenzyl pyrrolidines as human urotensin-II receptor antagonists. The ...synthesis, initial structure–activity relationships, and optimization of the initial hit that led to the identification of a truncated sub-series, represented by SB-436811 (
1a), are described.
High throughput screening of the corporate compound collection led to the discovery of a novel series of substituted aminoalkoxybenzyl pyrrolidines as human urotensin-II receptor antagonists. The synthesis, initial structure–activity relationships, and optimization of the initial hit that led to the identification of a truncated sub-series, represented by SB-436811 (
1a), are described.
The EXPEDITION study addressed the efficacy and safety of inhibiting the sodium hydrogen exchanger isoform-1 (NHE-1) by cariporide in the prevention of death or myocardial infarction (MI) in patients ...undergoing coronary artery bypass graft surgery. The premise was that inhibition of NHE-1 limits intracellcular Na accumulation and thereby limits Na/Ca-exchanger-mediated calcium overload to reduce infarct size.
High-risk coronary artery bypass graft surgery patients (n = 5,761) were randomly allocated to receive either intravenous cariporide (180 mg in a 1-hour preoperative loading dose, then 40 mg per hour over 24 hours and 20 mg per hour over the subsequent 24 hours) or placebo. The primary composite endpoint of death or MI was assessed at 5 days, and patients were followed for as long as 6 months.
At 5 days, the incidence of death or MI was reduced from 20.3% in the placebo group to 16.6% in the treatment group (p = 0.0002). Paradoxically, MI alone declined from 18.9% in the placebo group to 14.4% in the treatment group (p = 0.000005), while mortality alone increased from 1.5% in the placebo group to 2.2% with cariporide (p = 0.02). The increase in mortality was associated with an increase in cerebrovascular events. Unlike the salutary effects that were maintained at 6 months, the difference in mortality at 6 months was not significant.
The EXPEDITION study is the first phase III myocardial protection trial in which the primary endpoint was achieved and proof of concept demonstrated. As a result of increased mortality associated with an increase in cerebrovascular events, it is unlikely that cariporide will be used clinically. The findings suggest that sodium hydrogen exchanger isoform-1 inhibition holds promise for a new class of drugs that could significantly reduce myocardial injury associated with ischemia-reperfusion injury.
Highly potent CCR3 antagonists have been developed from a previously reported series of phenylalanine ester-based leads. Solution-phase, parallel synthesis optimization was utilized to identify ...highly potent, functional CCR3 antagonists.
Highly potent, functional CCR3 antagonists have been developed from a previously reported series of phenylalanine ester-based leads.
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