Structure–activity relationships of acyloxyamidine cytomegalovirus DNA polymerase inhibitors

Tucker, John; Clayton, Terrance L.; Chidester, C. G.; Schulz, M. W.; Harrington, Leigh E.; Conrad, Steven J.; Yagi, Yoshihiko; Oien, Nancee L.; Yurek, David A.; Kuo, Ming‐Shang

doi:10.1016/s0968-0896(99)00319-3

Cited by 27 publications

(17 citation statements)

References 19 publications

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“…Finally, a high-throughput screening (HTS) of the Pharmacia compound collection led to the identification of novel non-nucleoside inhibitors of HCMV DNA polymerase [85,86]. One of the compounds identified was acyloxyamidine 1 (a compound having two aryl groups joined by an acyloxyamidine linker).…”

Section: New Anti-hcmv Compounds That Target Ul54mentioning

confidence: 99%

“…One of the compounds identified was acyloxyamidine 1 (a compound having two aryl groups joined by an acyloxyamidine linker). Acyloxyamidine 1 ( Figure 4) competitively inhibited HCMV DNA polymerase with an IC 50 value of 20 mM and did not detectably inhibit human DNA polymerase at a concentration of 100 mM [85]. Another compound identified during the screening of the Pharmacia chemical library was a naphthalene-carboxamide, PNU-26370.…”

Section: New Anti-hcmv Compounds That Target Ul54mentioning

confidence: 99%

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Human cytomegalovirus DNA replication: antiviral targets and drugs

Mercorelli

Sinigalia

Loregian

et al. 2007

Reviews in Medical Virology

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Human cytomegalovirus (HCMV) infection is associated with severe morbidity and mortality in immunocompromised individuals, in particular transplant recipients and AIDS patients, and is the most frequent congenital viral infection in humans. There are currently five drugs approved for HCMV treatment: ganciclovir and its prodrug valganciclovir, foscarnet, cidofovir and fomivirsen. These drugs have provided a major advance in HCMV disease management, but they suffer from poor bioavailability, significant toxicity and limited effectiveness, mainly due to the development of drug resistance. Fortunately, there are several novel and potentially very effective new compounds which are under pre-clinical and clinical evaluation and may address these limitations. This review focuses on HCMV proteins that are directly or indirectly involved in viral DNA replication and represent already established or potential novel antiviral targets, and describes both currently available drugs and new compounds against such protein targets.

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Section: New Anti-hcmv Compounds That Target Ul54mentioning

confidence: 99%

Section: New Anti-hcmv Compounds That Target Ul54mentioning

confidence: 99%

Human cytomegalovirus DNA replication: antiviral targets and drugs

Mercorelli

Sinigalia

Loregian

et al. 2007

Reviews in Medical Virology

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“…Highthroughput screening of small molecules in the Pharmacia compound collection using the in vitro SPA assay identified several compounds as novel nonnucleoside inhibitors of the HCMV DNA polymerase (23,24). One of the more promising leads was PNU-26370, a naphthalene carboxamide (Fig.…”

Section: Resultsmentioning

confidence: 99%

Broad-Spectrum Antiherpes Activities of 4-Hydroxyquinoline Carboxamides, a Novel Class of Herpesvirus Polymerase Inhibitors

Oien¹,

Brideau²,

Hopkins³

et al. 2002

Antimicrob Agents Chemother

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While the treatment of herpes simplex virus type 2 (HSV-2) infections with acyclovir (ACV) and similar nucleoside analogs was one of the first success stories in antiviral chemotherapy, substantial unmet medical needs remain for diseases caused by herpesviruses. The increasing immunocompromised population, particularly AIDS patients and patients with transplants, has driven the need for improved antiviral agents to treat diseases caused by herpesviruses (6, 12). Although human cytomegalovirus (HCMV) is generally benign in the immunocompetent host, reactivation of HCMV is associated with significant morbidity and mortality in immunocompromised individuals. Active HCMV infection is associated with clinical syndromes such as pneumonia, retinitis, hepatitis, gastrointestinal disease, and congenital birth defects (2, 5, 7, 10, 12). The other human herpesviruses such as HSV-1, HSV-2, and varicella-zoster virus (VZV) also occur at a greater incidence and severity in the immunocompromised population (6, 17). Resistance to the currently available nucleoside analog antivirals does occur in this population, compounding the difficulty in treating these viral infections (11,18). Ganciclovir (GCV), foscarnet, cidofovir, and formivirsen, the only drugs approved for treatment of HCMV infections, are less than ideal agents due to their significant toxicity, modest efficacy, and poor oral bioavailability (3, 17). Clearly, less-toxic, orally available alternatives are needed for treating herpesvirus infections in immunocompromised patients. In order to address this unmet medical need, we initiated a program to identify novel nonnucleoside inhibitors of herpesvirus DNA polymerases through broad screening of our compound collection.Polymerases are classified according to their sequences and functional homologies. All herpesvirus polymerases belong to the family B DNA polymerases (1). Several eukaryotic polymerases, including human ␣ and ␦ polymerases, also belong to this family of DNA polymerases with human ␦ polymerase sharing the highest degree of homology with the herpesvirus polymerases (1). These family B DNA polymerases share six to seven highly conserved domains labeled I through VII, in decreasing order of conservation (8,9). In addition to these family B conserved domains, herpesvirus DNA polymerases share an additional conserved domain referred to as the A or ␦ domain (4). Hence, broad inhibition of herpesvirus polymerases may be possible if compounds target conserved domains shared among the herpesvirus polymerases but not shared among other eukaryotic polymerases such as human ␣ and ␦ DNA polymerases. Approximately 80,000 compounds were screened for inhibition of the HCMV polymerase. Since the goal was to identify DNA polymerase inhibitors that demonstrate broad activities against the herpesviruses with no activity against host cell DNA polymerases, active compounds were further evaluated for inhibition of the HSV-1 and VZV polymerases and human polymerases ␣, ␦, and ␥.One of the most promising leads from high-throughput

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“…Broad screening of the Pharmacia and Upjohn chemical library led to identi®cation of the acyloxyamidine 45 as a competitive inhibitor of the HCMV DNA polymerase. 72 Preliminary SAR investigation characterized this class by two aryl groups connected by an acyloxyamidine linker. Initial studies in which the two aryl groups were varied revealed little tolerance for modi®cation of the left hand 2,4-dichlorophenyl group, but replacing the right hand benzothiazole ring with a disubstituted isoxazole ring as in 46 (Fig.…”

Section: Nonnucleoside Hcmv Inhibitorsmentioning

confidence: 99%

Recent strategies in the development of new human cytomegalovirus inhibitors

Martı́nez¹,

Castro²,

Gil³

et al. 2001

Medicinal Research Reviews

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Human cytomegalovirus (HCMV) is one of the most common opportunistic infections in immunucompromised individuals, such as AIDS patients and organ transplant recipients, and is the most frequent congenital viral infection in humans. Despite a reduction of the incidence of AIDS‐related opportunistic infections in patients under highly active antiretroviral treatment, attention should be paid to the HCMV risk factor in these individuals. Furthermore, HCMV may have an important role in atherosclerosis. Existing antiviral treatments for the HCMV infection suffer from poor bioavailability, toxicity, and limited effectiveness, mainly due to the development of drug resistance. Fortunately there are novel and potentially very effective new compounds undergoing pre‐clinical and clinical evaluation. This review provides an overview in the last five years of new HCMV inhibitors (chemical structures, SAR, and new mechanisms of action) with the aim to provide new clues for the development of future drugs against this opportunistic virus. © 2001 John Wiley & Sons, Inc. Med Res Rev, 21, No. 3, 227–244, 2001

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Structure–activity relationships of acyloxyamidine cytomegalovirus DNA polymerase inhibitors

Cited by 27 publications

References 19 publications

Human cytomegalovirus DNA replication: antiviral targets and drugs

Human cytomegalovirus DNA replication: antiviral targets and drugs

Broad-Spectrum Antiherpes Activities of 4-Hydroxyquinoline Carboxamides, a Novel Class of Herpesvirus Polymerase Inhibitors

Recent strategies in the development of new human cytomegalovirus inhibitors

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