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Dive into the research topics where Francisco Velazquez is active.

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Featured researches published by Francisco Velazquez.


Bioorganic & Medicinal Chemistry Letters | 2011

I. Novel HCV NS5B polymerase inhibitors: discovery of indole 2-carboxylic acids with C3-heterocycles.

Gopinadhan N. Anilkumar; Charles A. Lesburg; Oleg Selyutin; Stuart B. Rosenblum; Qingbei Zeng; Yueheng Jiang; Tin Yau Chan; Haiyan Pu; Henry M. Vaccaro; Li Wang; Frank Bennett; Kevin X. Chen; Jose S. Duca; Stephen Gavalas; Yuhua Huang; Patrick Pinto; Mousumi Sannigrahi; Francisco Velazquez; Srikanth Venkatraman; Bancha Vibulbhan; Sony Agrawal; Nancy Butkiewicz; Boris Feld; Eric Ferrari; Zhiqing He; Chuan Kui Jiang; Robert E. Palermo; Patricia McMonagle; Hsueh-Cheng Huang; Neng Yang Shih

SAR development of indole-based palm site inhibitors of HCV NS5B polymerase exemplified by initial indole lead 1 (NS5B IC(50)=0.9 μM, replicon EC(50)>100 μM) is described. Structure-based drug design led to the incorporation of novel heterocyclic moieties at the indole C3-position which formed a bidentate interaction with the protein backbone. SAR development resulted in leads 7q (NS5B IC(50)=0.032 μM, replicon EC(50)=1.4 μM) and 7r (NS5B IC(50)=0.017 μM, replicon EC(50)=0.3 μM) with improved enzyme and replicon activity.


Bioorganic & Medicinal Chemistry Letters | 2012

II. Novel HCV NS5B polymerase inhibitors: discovery of indole C2 acyl sulfonamides.

Gopinadhan N. Anilkumar; Oleg Selyutin; Stuart B. Rosenblum; Qingbei Zeng; Yueheng Jiang; Tin-Yau Chan; Haiyan Pu; Li Wang; Frank Bennett; Kevin X. Chen; Charles A. Lesburg; Jose S. Duca; Stephen Gavalas; Yuhua Huang; Patrick Pinto; Mousumi Sannigrahi; Francisco Velazquez; Srikanth Venkatraman; Bancha Vibulbhan; Sony Agrawal; Eric Ferrari; Chuan-kui Jiang; Hsueh-Cheng Huang; Neng-Yang Shih; F. George Njoroge; Joseph A. Kozlowski

Development of SAR at the C2 position of indole lead 1, a palm site inhibitor of HCV NS5B polymerase (NS5B IC(50)=0.053μM, replicon EC(50)=4.8μM), is described. Initial screening identified an acyl sulfonamide moiety as an isostere for the C2 carboxylic acid group. Further SAR investigation resulted in identification of acyl sufonamide analog 7q (NS5B IC(50)=0.039μM, replicon EC(50)=0.011μM) with >100-fold improved replicon activity.


Bioorganic & Medicinal Chemistry Letters | 2012

5-Benzothiazole substituted pyrimidine derivatives as HCV replication (replicase) inhibitors

Ashok Arasappan; Frank Bennett; Vinay Girijavallabhan; Yuhua Huang; Regina Huelgas; Carmen Alvarez; Lei Chen; Stephen Gavalas; Seong-Heon Kim; Aneta Kosinski; Patrick Pinto; Razia Rizvi; Randall R. Rossman; Bandarpalle B. Shankar; Ling Tong; Francisco Velazquez; Srikanth Venkatraman; Vishal Verma; Joseph A. Kozlowski; Neng-Yang Shih; John J. Piwinski; Malcolm Maccoss; Cecil D. Kwong; Jeremy L. Clark; Anita T. Fowler; Feng Geng; Hollis S. Kezar; Abhijit Roychowdhury; Robert C. Reynolds; Joseph A. Maddry

Based on a previously identified HCV replication (replicase) inhibitor 1, SAR efforts were conducted around the pyrimidine core to improve the potency and pharmacokinetic profile of the inhibitors. A benzothiazole moiety was found to be the optimal substituent at the pyrimidine 5-position. Due to potential reactivity concern, the 4-chloro residue was replaced by a methyl group with some loss in potency and enhanced rat in vivo profile. Extensive investigations at the C-2 position resulted in identification of compound 16 that demonstrated very good replicon potency, selectivity and rodent plasma/target organ concentration. Inhibitor 16 also demonstrated good plasma levels and oral bioavailability in dogs, while monkey exposure was rather low. Chemistry optimization towards a practical route to install the benzothiazole moiety resulted in an efficient direct C-H arylation protocol.


Bioorganic & Medicinal Chemistry | 2014

Optimization of potency and pharmacokinetics of tricyclic indole derived inhibitors of HCV NS5B polymerase. Identification of ester prodrugs with improved oral pharmacokinetics

Srikanth Venkatraman; Francisco Velazquez; Stephen Gavalas; Wanli Wu; Kevin X. Chen; Anilkumar G. Nair; Frank Bennett; Yuhua Huang; Patrick Pinto; Yueheng Jiang; Oleg Selyutin; Bancha Vibulbhan; Qingbei Zeng; Charles A. Lesburg; Jose S. Duca; Larry Heimark; Hsueh-Cheng Huang; Sony Agrawal; Chuan-kui Jiang; Eric Ferrari; Cheng Li; Joseph A. Kozlowski; Stuart B. Rosenblum; Neng-Yang Shih; F. George Njoroge

HCV infections are the leading causes for hepatocellular carcinoma and liver transplantation in the United States. Recent advances in drug discovery have identified direct acting antivirals which have significantly improved cure rates in patients. Current efforts are directed towards identification of novel direct acting antiviral targeting different mechanism of actions which could become part of all oral therapies. We recently disclosed the identification of a novel tricyclic indole derived inhibitors of HCV NS5B polymerase that bound to the enzyme close to the active site. In this manuscript we describe further optimization of potency and pharmacokinetics (PK) of these inhibitors to identify compounds in low nM potency against gt-1b. These analogs also demonstrate excellent PK in rats and monkeys when administered as a dimethyl ethyl amino ester prodrug.


Bioorganic & Medicinal Chemistry Letters | 2013

Discovery of an irreversible HCV NS5B polymerase inhibitor

Qingbei Zeng; Anilkumar G. Nair; Stuart B. Rosenblum; Hsueh-Cheng Huang; Charles A. Lesburg; Yueheng Jiang; Oleg Selyutin; Tin-Yau Chan; Frank Bennett; Kevin X. Chen; Srikanth Venkatraman; Mousumi Sannigrahi; Francisco Velazquez; Jose S. Duca; Stephen Gavalas; Yuhua Huang; Haiyan Pu; Li Wang; Patrick Pinto; Bancha Vibulbhan; Sony Agrawal; Eric Ferrari; Chuan-kui Jiang; Cheng Li; David Hesk; Jennifer J. Gesell; Steve Sorota; Neng-Yang Shih; F. George Njoroge; Joseph A. Kozlowski

The discovery of lead compound 2e was described. Its covalent binding to HCV NS5B polymerase enzyme was investigated by X-ray analysis. The results of distribution, metabolism and pharmacokinetics were reported. Compound 2e was demonstrated to be potent (replicon GT-1b EC50 = 0.003 μM), highly selective, and safe in in vitro and in vivo assays.


Bioorganic & Medicinal Chemistry Letters | 2012

Synthesis and SAR of pyridothiazole substituted pyrimidine derived HCV replication inhibitors.

Vinay Girijavallabhan; Carmen Alvarez; Frank Bennett; Lei Chen; Stephen Gavalas; Yuhua Huang; Seong-Heon Kim; Aneta Kosinski; Patrick Pinto; Razia Rizvi; Randall R. Rossman; Bandarpalle B. Shankar; Ling Tong; Francisco Velazquez; Srikanth Venkatraman; Vishal Verma; Joseph A. Kozlowski; Neng-Yang Shih; John J. Piwinski; Malcolm Maccoss; Cecil D. Kwong; Namita Bansal; Jeremy L. Clark; Anita T. Fowler; Hollis S. Kezar; Jacob Valiyaveettil; Robert C. Reynolds; Joseph A. Maddry; Subramaniam Ananthan; John A. Secrist

Introduction of a nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzothiazole inhibitor 1, resulted in the discovery of the more potent pyridothiazole analogues 3. The potency and PK properties of the compounds were attenuated by the introductions of various functionalities at the R(1), R(2) or R(3) positions of the molecule (compound 3). Inhibitors 38 and 44 displayed excellent potency, selectivity (GAPDH/MTS CC(50)), PK parameters in all species studied, and cross genotype activity.


Bioorganic & Medicinal Chemistry | 2013

Discovery of novel tricyclic indole derived inhibitors of HCV NS5B RNA dependent RNA polymerase

Srikanth Venkatraman; Francisco Velazquez; Stephen Gavalas; Wanli Wu; Kevin X. Chen; Anilkumar G. Nair; Frank Bennett; Yuhua Huang; Patrick Pinto; Yueheng Jiang; Oleg Selyutin; Bancha Vibulbhan; Qingbei Zeng; Charles A. Lesburg; Jose S. Duca; Hsueh-Cheng Huang; Sony Agrawal; Chuan-kui Jiang; Eric Ferrari; Cheng Li; Joseph A. Kozlowski; Stuart B. Rosenblum; Neng-Yang Shih; F. George Njoroge

The characterization of HCV genome has identified various vital functional proteins involved in the life cycle of hepatitis C virus. This has resulted in many novel enzymatic targets that are potential for development of therapeutic agents. The HCV RNA dependent RNA polymerase (HCV NS5B) is one such essential enzyme for HCV replication that has been well characterized and studied by various groups to develop novel therapies for hepatitis C. In this paper, we describe our efforts towards the identification and structure-activity relationship (SAR) of novel tricyclic indole derivatives that bind close to the palm site of the NS5B polymerase. X-ray crystal structure of an inhibitor bound to the polymerase is also described.


Archive | 2008

Substituted indole derivatives and methods of use thereof

Gopinadhan N. Anilkumar; Frank Bennett; Tin-Yau Chan; Kevin X. Chen; Mousumi Sannigrahi; Francisco Velazquez; Srikanth Venkatraman; Qingbei Zeng; Jose S. Duca; Charles A. Lesburg; Joseph A. Kozlowski; F. George Njoroge; Stuart B. Rosenblum; Neng-Yang Shih


Archive | 2007

4,5-ring annulated indole derivatives for treating or preventing of hcv and related viral infections

Gopinadhan N. Anilkumar; Yueheng Jiang; Stuart B. Rosenblum; Srikanth Venkatraman; Francisco Velazquez; Neng-Yang Shih; F. George Njoroge; Joseph A. Kozlowski


Bioorganic & Medicinal Chemistry | 2010

Discovery of potent sulfonamide P4-capped ketoamide second generation inhibitors of hepatitis C virus NS3 serine protease with favorable pharmacokinetic profiles in preclinical species.

Stephane Bogen; Ashok Arasappan; Francisco Velazquez; Melissa Blackman; Regina Huelgas; Weidong Pan; Elise M. Siegel; Latha G. Nair; Srikanth Venkatraman; Zhuyan Guo; Ronald J. Doll; Neng-Yang Shih; F. George Njoroge

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