Molecular Properties That Influence the Oral Bioavailability of Drug Candidates

Veber, Daniel F.; Johnson, Stephen R.; Cheng, Hung‐Yuan; Smith, Brian R.; Ward, Keith W.; Kopple, Kenneth D.

doi:10.1021/jm020017n

Cited by 6,410 publications

(4,558 citation statements)

References 28 publications

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“…Generating 'good' multiple polar interactions (via hydrogen-bonds) is equally difficult as they need to be directional and precise [41,42]. Binding to Hsc70/Hsp70 via such interactions, whilst still trying to meet Lipinski [39] and Veber's [43] criteria of 'orally bioavailable drug-likeness', is extremely challenging. For example, in the case of VER-155008, trying to mimic these interactions has resulted in a compound with a high polar surface area (PSA, 164.4), the number of O?N atoms [10 (11) and a high molecular weight (555).…”

Section: Discussionmentioning

confidence: 99%

A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells

Massey¹,

Williamson²,

Browne³

et al. 2009

Cancer Chemother Pharmacol

273

254

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Purpose The anti-apoptotic function of the 70 kDa family of heat shock proteins and their role in cancer is well documented. Dual targeting of Hsc70 and Hsp70 with siRNA induces proteasome-dependent degradation of Hsp90 client proteins and extensive tumor specific apoptosis as well as the potentiation of tumor cell apoptosis following pharmacological Hsp90 inhibition. Methods We have previously described the discovery and synthesis of novel adenosine-derived inhibitors of the 70 kDa family of heat shock proteins; the first inhibitors described to target the ATPase binding domain. The in vitro activity of VER-155008 was evaluated in HCT116, HT29, BT474 and MDA-MB-468 carcinoma cell lines. Cell proliferation, cell apoptosis and caspase 3/7 activity was determined for VER-155008 in the absence or presence of small molecule Hsp90 inhibitors. Results VER-155008 inhibited the proliferation of human breast and colon cancer cell lines with GI 50 s in the range 5.3-14.4 lM, and induced Hsp90 client protein degradation in both HCT116 and BT474 cells. As a single agent, VER-155008 induced caspase-3/7 dependent apoptosis in BT474 cells and non-caspase dependent cell death in HCT116 cells. VER-155008 potentiated the apoptotic potential of a small molecule Hsp90 inhibitor in HCT116 but not HT29 or MDA-MB-468 cells. In vivo, VER-155008 demonstrated rapid metabolism and clearance, along with tumor levels below the predicted pharmacologically active level. Conclusion These data suggest that small molecule inhibitors of Hsc70/Hsp70 phenotypically mimic the cellular mode of action of a small molecule Hsp90 inhibitor and can potentiate the apoptotic potential of a small molecule Hsp90 inhibitor in certain cell lines. The factors determining whether or not cells apoptose in response to Hsp90 inhibition or the combination of Hsp90 plus Hsc70/ Hsp70 inhibition remain to be determined.

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Section: Discussionmentioning

confidence: 99%

A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells

Massey¹,

Williamson²,

Browne³

et al. 2009

Cancer Chemother Pharmacol

273

254

View full text Add to dashboard Cite

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“…3 Additionally, our recent findings on the improved liver-stage antimalarial activity of N-cinnamoyl derivatives of primaquine 4 motivated us to evaluate the activity of compounds 6c, 6d and 6f against liver-stage P. berghei parasites ( Fig. 2); the compounds were chosen according to: (i) their antiplasmodial activity against the erythrocytic stage, 6c being the most active; (ii) their prospective propensity to present low cytotoxicity, 6d being the most active compound complying with lead-likeness properties, 13 Lipinski's Rule of Five, 14 and Veber filter, 15 and (iii) their likelihood of good metabolic stability, solubility and bioavailability, the cinnamic ring of 6f being substituted with a fluorine atom, which is known for its ability to increase the aforementioned properties when incorporated into aromatic organic compounds. 16 Remarkably, the three test compounds were more potent than primaquine (PQ), the reference drug for the parasite liver stage, and compounds 6d and 6f were non-toxic to Huh7 human hepatoma cells in vitro at up to 5 lM, as shown by cell confluency analysis ( Fig.…”

Section: Introductionmentioning

confidence: 99%

In vitro efficiency of 9-(N-cinnamoylbutyl)aminoacridines against blood- and liver-stage malaria parasites

Pérez

Teixeira

Gomes

et al. 2013

Bioorganic & Medicinal Chemistry Letters

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a b s t r a c tNovel 9-aminoacridine derivatives were synthesized by linking the heteroaromatic core to different cinnamic acids through an aminobutyl chain. The test compounds demonstrated mid-nanomolar in vitro activity against erythrocytic stages of the chloroquine-resistant W2 strain of the human malaria parasite Plasmodium falciparum. Two of the most active derivatives also showed in vitro activity against liver-stage Plasmodium berghei, with activity greater than that of the reference liver-stage antimalarial primaquine.The compounds were not toxic to human hepatoma cells at concentrations up to 5 lM. Hence, 9-(N-cinnamoylbutyl)aminoacridines are a new class of leads for prevention and treatment of malaria.

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“…However, the large number of rotatable bonds inherent in the lysine-based scaffold and PSA exceeding 100 for some potent compounds (particularly the 2-piperazinylpyridines) were concerns for oral bioavailability. 24 A key tactic employed to reduce the number of rotatable bonds was lysine scaffold replacement. Early attempts resulted in 4-aminophenylalanine-based 5 and piperidinylalanine-based 6 ( Figure 2); however, both were inactive against TG2 when tested at 80 μM, and comparisons with the potencies of B, 4p, and 8a argued against synthesis of additional analogues.…”

mentioning

confidence: 99%

SAR Development of Lysine-Based Irreversible Inhibitors of Transglutaminase 2 for Huntington's Disease

Wityak

Prime

Brookfield

et al. 2012

ACS Med. Chem. Lett.

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ABSTRACT:We report a series of irreversible transglutaminase 2 inhibitors starting from a known lysine dipeptide bearing an acrylamide warhead. We established new SARs resulting in compounds demonstrating improved potency and better physical and calculated properties. Transglutaminase selectivity profiling and in vitro ADME properties of selected compounds are also reported.KEYWORDS: plasma stability, polar surface area, acrylamides, celiac disease, in vitro ADME T issue transglutaminase 2 (TG2) is a multifunctional enzyme primarily known for its calcium-dependent protein cross-linking activity. 1 Less well-studied functions include simple amidase, GTPase, ATPase, and protein disulfide isomerase activities. 2−4 TG2 has been characterized in at least three forms, including open, 5 closed, 6 and an open-inactive form. 7 Genetic deletion of TG2 in mice suggests a role for TG2 activity in mitochondrial energy function, 8 and its overactivity has been most closely associated with celiac disease and Huntington's disease (HD). In addition, there is growing support for roles in inflammation and cancer. 9−12 HD is an autosomal dominant, progressive, neurodegenerative disease that is characterized clinically by motor, cognitive, and behavioral deficits. 13 TG2 expression and transglutaminase activity have been shown to be increased in the brains of HD patients, 14 and in vitro and in vivo models have implicated TG2 in HD pathophysiology, 15−18 although more recent contradictory animal data have appeared. 19 The subject of irreversible inhibitors of TG2 has been recently reviewed. 20 Our studies have focused on irreversible inhibitors bearing an acrylamide warhead, 21,22 during which we became interested in dipeptides A and B 23 (Figure 1) as leads due to their attractive potency and specificity for TG2. In a prior report, 21 we established that an excellent correlation exists for several transglutaminase isoforms between the IC 50 values using a 30 min compound incubation and the irreversible inhibition constants, k inact /K i . With this correlation in hand, we relied on the IC 50 values to guide our medicinal chemistry effort. We began by benchmarking dipeptide A, resulting in the selectivity profile illustrated in Figure 1. We also resynthesized and tested several compounds from the Marrano paper, 23 the results of which are found in the Supporting Information. To summarize, the results confirmed that dipeptide A was one of the most potent TG2 inhibitors from this report. As shown in Figure 1, ADME profiling studies on this compound indicated good solubility, low permeability potentially accompanied by efflux, and rapid metabolism in mouse liver microsomes (mLM). Our goal was to identify a tool molecule from this series for in vivo proof of concept studies in HD, where brain is the target organ. Therefore, we focused on increasing potency, improving the absorption profile, and increasing microsomal stability. Lowering the polar surface area (PSA), the number of hydrogen bond donors, and the number of rotatable bon...

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Molecular Properties That Influence the Oral Bioavailability of Drug Candidates

Cited by 6,410 publications

References 28 publications

A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells

A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells

In vitro efficiency of 9-(N-cinnamoylbutyl)aminoacridines against blood- and liver-stage malaria parasites

SAR Development of Lysine-Based Irreversible Inhibitors of Transglutaminase 2 for Huntington's Disease

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