Discovery of pyrido[2,3-d]pyrimidine-based inhibitors of HCV NS5A

DeGoey, David A.; Betebenner, David A.; Grampovnik, David J.; Liu, Dachun; Pratt, John K.; Tufano, Michael D.; He, Wenping; Krishnan, Preethi; Pilot‐Matias, Tami; Marsh, Kennan C.; Molla, Akhteruzzaman; Kempf, Dale J.; Maring, Clarence J.

doi:10.1016/j.bmcl.2013.04.009

Cited by 47 publications

(38 citation statements)

References 9 publications

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“…Several NS5A inhibitors, including daclatasvir, ledipasvir, samatasvir, GS5816, GSK-2336805, PPI461, PPI668, ACH-2928, ACH-3102, and MK-8742, are currently in various stages of clinical development (25). Our efforts to identify inhibitors of HCV replication led to identification of naphthyridine compounds that lacked activity against the HCV NS3/4A protease and NS5B polymerase enzymes (26,27). Based on the selection pattern of resistance variants, the naphthyridine inhibitors were shown to target HCV NS5A in the HCV cell-based replicon system.…”

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“…Based on the selection pattern of resistance variants, the naphthyridine inhibitors were shown to target HCV NS5A in the HCV cell-based replicon system. A subsequent proof-of-concept study with a naphthyridine analog in a chimpanzee resulted in a robust HCV RNA viral load decline, and resistance analysis confirmed NS5A as the drug target (27). Structure-activity relationship studies and optimization of N-phenylpyrrolidine-based inhibitors led to the discovery of ABT-267, now known as ombitasvir ( Fig.…”

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In Vitro and In Vivo Antiviral Activity and Resistance Profile of Ombitasvir, an Inhibitor of Hepatitis C Virus NS5A

Krishnan

Beyer

Mistry

et al. 2015

Antimicrob Agents Chemother

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Ombitasvir (ABT-267) is a hepatitis C virus (HCV) NS5A inhibitor with picomolar potency, pan-genotypic activity, and 50% effective concentrations (EC 50 s) of 0.82 to 19.3 pM against HCV genotypes 1 to 5 and 366 pM against genotype 6a. Ombitasvir retained these levels of potency against a panel of 69 genotype 1 to 6 chimeric replicons containing the NS5A gene derived from HCV-infected patients, despite the existence of natural sequence diversity within NS5A. In vitro resistance selection identified variants that conferred resistance to ombitasvir in the HCV NS5A gene at amino acid positions 28, 30, 31, 58, and 93 in genotypes 1 to 6. Ombitasvir was evaluated in vivo in a 3-day monotherapy study in 12 HCV genotype 1-infected patients at 5, 25, 50, or 200 mg dosed once daily. All patients in the study were HCV genotype 1a infected and were without preexisting resistant variants at baseline as determined by clonal sequencing. Decreases in HCV RNA up to 3.1 log 10 IU/ml were observed. Resistance-associated variants at position 28, 30, or 93 in NS5A were detected in patient samples 48 hours after the first dose. Clonal sequencing analysis indicated that wild-type virus was largely suppressed by ombitasvir during 3-day monotherapy, and at doses higher than 5 mg, resistant variant M28V was also suppressed. Ombitasvir was well tolerated at all doses, and there were no serious or severe adverse events. HCV genotype 1, predominant in North America, Europe, and Japan, accounts for 60% of the global infections (4-6). Genotype 2 infections are most prevalent in North America, Europe, and Japan, while genotype 3, 6, and 7 infections are predominant within various parts of Southeast Asia (3, 7-9). In Egypt, HCV infections are almost exclusively genotype 4, while genotype 5 is common in South Africa (10, 11). The levels of nucleotide sequence diversity between genotypes and between subtypes are 30 to 35% and 20 to 25%, respectively (12). The viral dynamics are rapid for HCV, with 10 12 virions being produced daily with a half-life of 45 min (13). Moreover, the RNA-dependent RNA polymerase of HCV is intrinsically error prone, and its lack of a proofreading function allows for introduction of approximately one nucleotide change per genome per replication cycle, which under drug pressure results in the expansion of preexisting drug resistant variants (13). These factors have created challenges in developing pan-genotypic HCV inhibitors with high genetic barriers to the development of resistance.HCV replication can be inhibited at various points in the replication cycle by targeting viral or host cell functions (14,15). For the treatment of HCV genotype 1, three HCV NS3/4A protease inhibitors (telaprevir, boceprevir, and simeprevir) and one nucleoside NS5B polymerase inhibitor (sofosbuvir), each in combination with pegylated interferon (pegIFN) and ribavirin (RBV), have received marketing approval in the United States and Europe. The sustained virologic response (SVR) rate increased from 40 to 52% with pegIFN and RBV regimens to 67...

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confidence: 99%

In Vitro and In Vivo Antiviral Activity and Resistance Profile of Ombitasvir, an Inhibitor of Hepatitis C Virus NS5A

Krishnan

Beyer

Mistry

et al. 2015

Antimicrob Agents Chemother

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128

136

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“…The pyridopyrimidine compounds were exhibited good oral bioavailability examined in rats and dogs. The compound 39 (A-972338) was selected and studied in HCV infected chimpanzee (Degoey et al, 2013).…”

Section: Anti-infectious Agentsmentioning

confidence: 99%

An overview on synthetic and pharmaceutical prospective of pyrido[2,3‐d]pyrimidines scaffold

Yadav

Shah

2020

Chem Biol Drug Des

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Pyrido[2,3-d]pyrimidine, a fused hetero-bicyclic nucleus containing pyridine and pyrimidine rings has attained the momentary attention in the sphere of multicomponent synthetic protocol and medicinal chemist. Pyrido[2,3-d]pyrimidine derived drugs have manifested diverse pharmacological activities, particularly, anti-inflammatory, cytotoxic, antimicrobial, phosphodiesterase inhibitors and cytokine inhibitors etc. The present review illustrates various modern synthetic strategies adopted, the structure-activity relationship (SAR) aspects and discloses the extensive crucial biological properties (anticancer, anti-infectious, anti-diabetics and CNS agents) of pyrido[2,3-d]pyrimidines. K E Y W O R D S anticancer, anti-diabetics, anti-infectious, CNS agents, pyrido[2,3-d]pyrimidines How to cite this article: Yadav P, Shah K. An overview on synthetic and pharmaceutical prospective of pyrido[2,3-d]pyrimidines scaffold.

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“…Pyrido [2,3-d]pyrimidine is one of the most privileged heterocyclic frameworks in several efficacious pharmacological compounds. Pyrido [2,3-d]pyrimidine ring systems have assorted biological and pharmacological activities such as being analgesic, anti-inflammatory [1-3], antitubercular [4], antimicrobial [5][6][7], a threonine tyrosine kinase (TTK) inhibitor [8], an adenosine kinase inhibitor [9], antiviral [10], antioxidant [11][12][13][14], a dihydrofolate reductase inhibitor [15,16], and an efficient glucosidase inhibitor [17,18]. Moreover, the 1,3-benzothiazole nucleus is a highly significant scaffold in the drug design, due to important pharmacological and medicinal activities, such as being antiviral [19], antituberculosis [20], an identifier of selective CB2 receptor ligands [21], antitumor [22][23][24], antimicrobial [25][26][27], anticonvulsant [28], a schistosome BCL-2 inhibitor [29], antidiabetic [30], antioxidant [31], an anti-Alzheimer drug [32] and a urease inhibitor [33] among the heterocyclic compounds containing a pyrimidine and benzothiazole nucleus that exhibits biological activity [34][35][36] (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antimicrobial, Anticancer and Anti-Oxidant Activities of Novel 2,3-Dihydropyrido[2,3-d]pyrimidine-4-one and Pyrrolo[2,1-b][1,3]benzothiazole Derivatives via Microwave-Assisted Synthesis

et al. 2022

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In our attempt towards the synthesis and development of effective antimicrobial, anticancer and antioxidant agents, a novel series of 2,3-dihydropyrido[2,3-d]pyrimidin-4-one 7a–e and pyrrolo[2,1-b][1,3]benzothiazoles 9a–e were synthesized. The synthesis of 2-(1,3-benzo thiazol-2-yl)-3-(aryl)prop-2-enenitrile (5a–e) as the key intermediate was accomplished by a microwave efficient method. Via a new variety oriented synthetic microwave pathway, these highly functionalized building blocks allowed access to numerous fused heteroaromatic such as 7-amino-6-(1,3-benzo thiazol-2-yl)-5-(aryl)-2-thioxo-2,3dihydropyrido [2,3-d]pyrimidin-4(1H)-one 7a–e and 1-amino-2-(aryl)pyrrolo[2,1-b][1,3]benzothiazole-3-carbonitrile derivatives 9a–e in order to study their antimicrobial and anticancer activity. The present investigation offers effective and rapid new procedures for the synthesis of the newly polycondensed heterocyclic ring systems. All the newly synthesized compounds were evaluated for antimicrobial, anticancer and antioxidant activity. Compounds 7a,d, and 9a,d showed higher antimicrobial activity than cefotaxime and fluconazole while the remaining compounds exhibited good to moderate activity against bacteria and fungi. An anticancer evaluation of the newly synthesized compounds against the three tumor cell lines (lung cell NCI-H460, liver cancer HepG2 and colon cancer HCT-116) exhibited that compounds 7a, d, and 9a,d have higher cytotoxicity against the three human cell lines compared to doxorubicin as a reference drug. These compounds also exhibited higher antioxidant activity and a great ability to protect DNA from damage induced by bleomycin.

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Discovery of pyrido[2,3-d]pyrimidine-based inhibitors of HCV NS5A

Cited by 47 publications

References 9 publications

In Vitro and In Vivo Antiviral Activity and Resistance Profile of Ombitasvir, an Inhibitor of Hepatitis C Virus NS5A

In Vitro and In Vivo Antiviral Activity and Resistance Profile of Ombitasvir, an Inhibitor of Hepatitis C Virus NS5A

An overview on synthetic and pharmaceutical prospective of pyrido[2,3‐d]pyrimidines scaffold

Synthesis and Antimicrobial, Anticancer and Anti-Oxidant Activities of Novel 2,3-Dihydropyrido[2,3-d]pyrimidine-4-one and Pyrrolo[2,1-b][1,3]benzothiazole Derivatives via Microwave-Assisted Synthesis

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