Optimization of orally bioavailable alkyl amine renin inhibitors

Xu, Zhixiang; Cacatian, Salvacion; Yuan, Jing; Simpson, R. David; Jia, Lanqi; Zhao, Wei; Tice, Colin M.; Flaherty, Patrick; Guo, Joan; Ishchenko, Alexey; Singh, Suresh B.; Wu, Zhenyong; McKeever, Brian; Scott, Boyd B.; Bukhtiyarov, Yuri; Berbaum, Jennifer; Mason, J. L.; Panemangalore, Reshma; Cappiello, Maria Grazia; Bentley, Ross; Doe, Christopher P.; Harrison, Richard K.; McGeehan, Gerard M.; Dillard, Lawrence W.; Baldwin, John J.; Claremon, David A.

doi:10.1016/j.bmcl.2009.11.066

Cited by 18 publications

(40 citation statements)

References 16 publications

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“…The solubility of aliskiren at pH 6.5 suggested that it was soluble in the intestine ( Table 1). The F of 1.8% was similar to that of previously reported values (1.4%) [17] and to that in humans (2.6%) [2,3]. The urinary excretion of aliskiren in monkeys after its intravenous administration was very low (f e 0-t h : 0.029) ( Table 6).…”

Section: Discussionsupporting

confidence: 88%

Effects of the inhibition of intestinal P‐glycoprotein on aliskiren pharmacokinetics in cynomolgus monkeys

Tsukimoto

Ohashi²,

Torimoto³

et al. 2014

Biopharm & Drug Disp

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Aliskiren is a substrate for P-glycoprotein (P-gp) and is metabolized via cytochrome P450 3A4 (CYP3A4). The aim of the present study was to assess whether P-gp influenced the pharmacokinetics of aliskiren and also if drug-drug interactions (DDIs) mediated through P-gp could be reproduced in cynomolgus monkeys. The study investigated the pharmacokinetics of aliskiren in mdr1a/1b gene-deficient (P-gp KO) and wild-type (WT) mice. The area under the plasma concentration-time curve (AUC) following the oral administration of aliskiren was 6.9-fold higher in P-gp KO mice than in WT mice, while no significant differences were observed in the AUC or total plasma clearance following the intravenous administration of aliskiren to P-gp KO mice. Then the pharmacokinetics of aliskiren were evaluated and DDIs between aliskiren and P-gp inhibitors, such as cyclosporin A (CsA) and zosuquidar, examined in cynomolgus monkeys. The AUC for aliskiren were 8.3- and 42.1-fold higher after the oral administration of aliskiren with the concomitant oral administration of zosuquidar and CsA at doses of 10 and 30 mg/kg, respectively. In contrast, the AUC after the intravenous and oral administration of aliskiren was not significantly affected by the oral administration of zosuquidar or intravenous administration of CsA, respectively. These results indicated that P-gp strictly limited the intestinal absorption of aliskiren in mice and monkeys, and also that the effects of intestinal P-gp inhibition by CsA or zosuquidar on the pharmacokinetics of aliskiren were sensitively reproduced in monkeys. In conclusion, aliskiren can be used as a sensitive substrate to evaluate intestinal P-gp inhibition in monkeys.

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Section: Discussionsupporting

confidence: 88%

Effects of the inhibition of intestinal P‐glycoprotein on aliskiren pharmacokinetics in cynomolgus monkeys

Tsukimoto

Ohashi²,

Torimoto³

et al. 2014

Biopharm & Drug Disp

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“…This trend can be explained based on the fact that most reported potent renin inhibitors (including those in our training list) tend to have large molecular sizes Table 6 The training compounds used for adding excluded spheres for Hypo1/5 and Hypo1/7 using HIPHOP-REFINE module of CATALYST. (of MW > 600) [16,18,7,19,[63][64][65] and therefore require wellbalanced combination of hydrophobic and hydrophilic groups. Lack of such balance for such large molecules can lead to excessive hydration at one end, or poor water-solubility at the other, which in both cases seem to undermine their affinities to renin.…”

Section: Qsar Modelingmentioning

confidence: 99%

“…The first renin crystallographic structure was determined by Sialecki et al at a resolution of 2.5Å [15]. Subsequent crystallographic studies achieved better resolutions [16][17][18][19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Discovery of new renin inhibitory leads via sequential pharmacophore modeling, QSAR analysis, in silico screening and in vitro evaluation

Al-Nadaf

Taha

2011

Journal of Molecular Graphics and Modelling

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“…ABCB1 is a member of the ATP‐binding cassette family of drug transporters involved in the efflux of a large range of drugs, such as anticancer drugs (daunorubicin, paclitaxel and tamoxifen), antiallergics (terfenadine), antibiotics (cefazolin and cefoperazon), cardiacs (propafenone, digoxin and quinidine), HIV protease inhibitors (indinavir and ritonavir), renin inhibitor (aliskiren) and steroids (aldosterone and dexamethasone) (Brinkmann & Eichelbaum, ). Pharmacokinetic studies have reportedly indicated that aliskiren showed low bioavailability (16%) in marmosets (Waldmeier et al, ), similar to cynomolgus monkeys (1.4%) (Xu et al, ) and humans (2.6%) (Azizi, Webb, Nussberger, & Hollenberg, ), and was predominantly eliminated by biliary/fecal excretion, and was largely recovered in the feces of marmosets with intravenous dosing as unchanged aliskiren (up to 78%) (Waldmeier et al, ), but the contribution of efflux transporters for these properties has not been elucidated. Because of the importance in pharmacokinetics, ABCB1 orthologs have been identified in various species including humans, pigs, dogs, rats, hamsters, and mice (Chen et al, ; Devault & Gros, ; Endicott, Sarangi, & Ling, ; Guo et al, ; Silverman, Raunio, Gant, & Thorgeirsson, ; Steingold et al, ; Ueda et al, ).…”

Section: Introductionmentioning

confidence: 99%

Molecular cloning and tissue distribution of a novel marmoset ABC transporter

Uehara

Uno

Inoue

et al. 2017

Biopharm & Drug Disp

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Common marmosets (Callithrix jacchus) have been recognized as a useful small non-human primate model in preclinical testing for drug development. In this study, a cDNA of novel ATPdependent efflux transporter ABCB1 was cloned from marmoset liver tissue. Marmoset ABCB1 cDNA encodes a protein of 1279 amino acid residues (MW = 141.4 kDa) containing characteristic regions of an ATP-binding cassette (ABC) protein, two hydrophobic transmembrane regions and two cytoplasmic nucleotide-binding regions, similar to human ABCB1. The deduced amino acid sequences were more highly identical (95%) to those of human ABCB1 compared with non-primate species such as dogs, pigs and rodents (79-90%). A close evolutionary relationship of ABCB1 among marmosets, cynomolgus and rhesus monkeys and humans was evident from a phylogenetic analysis using ABCB1 amino acid sequences from primates, dogs, pigs and rodents. Tissue distribution analyses by quantitative reverse transcription-polymerase chain reaction indicated that marmoset ABCB1 mRNA was most abundant in kidneys, followed by small intestines and livers, similar to human ABCB1, and marmoset ABCB1 proteins in these tissues were also detected by immunoblotting. These results indicated that the primary structure and tissue distribution of ABCB1 in marmosets were similar to those of humans, suggesting similar molecular characteristics of ABCB1 between marmosets and humans.

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Optimization of orally bioavailable alkyl amine renin inhibitors

Cited by 18 publications

References 16 publications

Effects of the inhibition of intestinal P‐glycoprotein on aliskiren pharmacokinetics in cynomolgus monkeys

Effects of the inhibition of intestinal P‐glycoprotein on aliskiren pharmacokinetics in cynomolgus monkeys

Discovery of new renin inhibitory leads via sequential pharmacophore modeling, QSAR analysis, in silico screening and in vitro evaluation

Molecular cloning and tissue distribution of a novel marmoset ABC transporter

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