Synthesis of C-6 substituted pyrazolo[1,5-a]pyridines with potent activity against herpesviruses.

A novel series of potent C-6 substituted pyrazolo[1,5-a]pyridine inhibitors of herpes simplex viruses has been identified. A synthetic methodology was developed involving functionalization of a C-6 trifluoromethyl pyrazolo[1,5-a]pyridine to allow facile access to a diverse set of analogues from common late stage intermediates. The expansion of the SAR of this series at the 6 position allows for modifications to developability parameters such as clogP, while maintaining potency comparable to acyclovir.

Pyrazolopyridine antiherpetics: SAR of C2' and C7 amine substituents.

A novel series of potent pyrazolo[1,5-a]pyridine inhibitors of herpes simplex virus 1 replication have been identified. Several complimentary synthetic methods were developed to allow facile access to a diverse set of analogs from common late stage intermediates. Detailed examination of the amine substituents at the C2' position of the pyrimidine and C7 position of the core pyrazolopyridine is described. The antiviral data suggests that non-polar amines are preferred for optimal activity. Additionally, the 2' position has been shown to require an NH group to retain activity levels similar to that of the gold standard acyclovir.

Synthesis of novel substituted 2-phenylpyrazolopyridines with potent activity against herpesviruses.

Herpesviruses are a significant source of human disease; amongst these herpes simplex virus 1 (HSV-1) and HSV-2 are very prevalent and cause recurrent infections. We recently identified a pyrazolo[1,5-a]pyridine scaffold that showed promising activity against HSV-1 and HSV-2 in Vero cell antiviral assays. Here, we describe the synthesis and anti-herpetic activity of several 3-pyrimidinyl-2-phenylpyrazolo[1,5-a]pyridines with differing 2-phenyl substitution patterns. Approaches to rapidly access a number of analogs with different 2-phenyl substitution patterns are outlined. Several of the compounds described have comparable activity to acyclovir against HSV-1 and HSV-2.

Antiviral activity of GW678248, a novel benzophenone nonnucleoside reverse transcriptase inhibitor.

The compound GW678248 is a novel benzophenone nonnucleoside reverse transcriptase inhibitor (NNRTI). Preclinical assessment of GW678248 indicates that this compound potently inhibits wild-type (WT) and mutant human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in biochemical assays, with 50% inhibitory concentrations (IC(50)s) between 0.8 and 6.8 nM. In HeLa CD4 MAGI cell culture virus replication assays, GW678248 has an IC(50) of < or =21 nM against HIV-1 isogenic strains with single or double mutations known to be associated with NNRTI resistance, including L100I, K101E, K103N, V106A/I/M, V108I, E138K, Y181C, Y188C, Y188L, G190A/E, P225H, and P236L and various combinations. An IC(50) of 86 nM was obtained with a mutant virus having V106I, E138K, and P236L mutations that resulted from serial passage of WT virus in the presence of GW678248. The presence of 45 mg/ml human serum albumin plus 1 mg/ml alpha-1 acid glycoprotein increased the IC(50) approximately sevenfold. Cytotoxicity studies with GW678248 indicate that the 50% cytotoxicity concentration is greater than the level of compound solubility and provides a selectivity index of >2,500-fold for WT, Y181C, or K103N HIV-1. This compound exhibits excellent preclinical antiviral properties and, as a prodrug designated GW695634, is being developed as a new generation of NNRTI for the treatment of HIV-1 in combination with other antiretroviral agents.

Interactions of 1263W94 with other antiviral agents in inhibition of human cytomegalovirus replication.

Inhibition of human cytomegalovirus (HCMV) by 1263W94 was additive dosewise in combination with ganciclovir, acyclovir, and foscarnet. None of the commonly used anti-human immunodeficiency virus agents antagonized the inhibition of HCMV by 1263W94. The data were analyzed by a modified isobologram procedure that measures the strength and statistical significance of drug interactions.

Mechanism of action of the ribopyranoside benzimidazole GW275175X against human cytomegalovirus.

New human cytomegalovirus (HCMV) therapies with novel mechanisms of action are needed to treat drug-resistant HCMV that arises during therapy with currently approved agents. 2-Bromo-5,6-dichloro-1-beta-D-ribofuranosyl-1H-benzimidazole (BDCRB) is an effective anti-HCMV agent with a novel mechanism of action, but problems with in vivo stability preclude clinical development. A D-ribopyranosyl derivative of BDCRB, GW275175X, displays similar antiviral activity without the in vivo stability problems. We present an initial description of the activity of GW275175X against HCMV, other herpesviruses, and selected nonherpesviruses. In addition, we show that it acts as a DNA maturation inhibitor like the parent compound, BDCRB, rather than via the mechanisms of action of 1263W94 or any anti-HCMV drugs approved for marketing. GW275175X is a promising candidate for clinical development as an anti-HCMV agent.