Improving non-nucleoside reverse transcriptase inhibitors for first-line treatment of HIV infection: The development pipeline and recent clinical data

Current Opinion in Drug Discovery and Development

Volumn 11, Issue 4, 2008, Pages 458-470

  Sweeney, Z K ^a   Klumpp, K ^a  

^a Roche Palo Alto ^*  (United States)

Author keywords

Efavirenz; IDX 899; MK 4965; Nevirapine; NNRTI; RDEA 806; Rilpivirine; TMC 278; UK 453061

Indexed keywords

AMPRENAVIR; DELAVIRDINE; EFAVIRENZ; EFAVIRENZ PLUS EMTRICITABINE PLUS TENOFOVIR DISOPROXIL; ETHER DERIVATIVE; ETRAVIRINE; GW 695634; IDX 899; LAMIVUDINE; LOPINAVIR PLUS RITONAVIR; MARAVIROC; MK 4965; NEVIRAPINE; PROTEINASE INHIBITOR; PYRIDONE DERIVATIVE; R 1206; RALTEGRAVIR; RDEA 806; RILPIVIRINE; RITONAVIR; RNA DIRECTED DNA POLYMERASE INHIBITOR; RO 0335; STAVUDINE; THIOCARBAMIC ACID DERIVATIVE; UK 453061;

ANTIBIOTIC RESISTANCE; CENTRAL NERVOUS SYSTEM DISEASE; CHOLESTEROL BLOOD LEVEL; CLINICAL TRIAL; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG EFFECT; DRUG EFFICACY; DRUG HALF LIFE; DRUG POTENCY; DRUG RESPONSE; DRUG STRUCTURE; DRUG WITHDRAWAL; GASTROINTESTINAL SYMPTOM; HEPATITIS; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; HYPERSENSITIVITY REACTION; LIVER TOXICITY; MENTAL DISEASE; METABOLIC DISORDER; NEURAL TUBE DEFECT; NEUROLOGIC DISEASE; PATIENT COMPLIANCE; RASH; REVIEW; SIDE EFFECT; SKIN MANIFESTATION; STEVENS JOHNSON SYNDROME; TERATOGENICITY; TREATMENT OUTCOME; TRIACYLGLYCEROL BLOOD LEVEL; VERTIGO; VIRUS INHIBITION; VIRUS MUTANT; VIRUS REPLICATION;

ANIMALS; ANTI-HIV AGENTS; DRUG DESIGN; HUMANS; MOLECULAR STRUCTURE; NITRILES; PYRIMIDINES; REVERSE TRANSCRIPTASE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP; TREATMENT OUTCOME;

EID: 46749104685     PISSN: 13676733     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (95)

1. Flexner C: HIV drug development: The next 25 years. Nat Rev Drug Discov (2007) 6(12):959-966. • Reviews current strategies for the treatment of HIV, the potential of new drug classes to affect the preferred HIV treatment options, and the causes and consequences of drug resistance.
2. Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T: Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS (2001) 15(1):71-75.
3. de Vries-Sluijs TE, Dieleman JP, Arts D, Huitema AD, Beijnen JH, Schutten M, van der Ende ME: Low nevirapine plasma concentrations predict virological failure in an unselected HIV-1-infected population. Clin Pharmacokinet (2003) 42(6):599-605.
4. Leth FV, Kappelhoff BS, Johnson D, Losso MH, Boron-Kaczmarska A, Saag MS, Livrozet JM, Hall DB, Leith J, Huitema AD, Wit FW et al: Pharmacokinetic parameters of nevirapine and efavirenz in relation to antiretroviral efficacy. AIDS Res Hum Retroviruses (2006) 22(3):232-239.
5. Kirk O, Katzenstein TL, Gerstoft J, Mathiesen L, Nielsen H, Pedersen C, Lundgren JD: Combination therapy containing ritonavir plus saquinavir has superior short-term antiretroviral efficacy: A randomized trial. AIDS (1999) 13(1):F9-F16.
6. Duval X, Lamotte C, Race E, Descamps D, Damond F, Clavel F, Leport C, Peytavin G, Vilde JL: Amprenavir inhibitory quotient and virological response in human immunodeficiency virus-infected patients on an amprenavir-containing salvage regimen without or with ritonavir. Antimicrob Agents Chemother (2002) 46(2): 570-574.
7. Lichterfeld M, Wöhrmann A, Schmeisser N, Fätkenheuer G, Salzberger B, Wyen C, Schmitz K, Sauerbruch T, Rockstroh JK: Superior virological efficacy of ritonavir-boosted protease inhibitor regimens compared to single protease inhibitor therapy. Eur J Med Res (2003) 8(2):56-60.
8. Maggiolo F, Airoldi M, Kleinloog HD, Callegaro A, Ravasio V, Arici C, Bombana E, Suter F: Effect of adherence to HAART on virologic outcome and on the selection of resistance-conferring mutations in NNRTI- or PI-treated patients. HIV Clin Trials (2007) 8(5):282-292. •• This prospective study effectively relates adherence and drug pharmacokinetics to viral failure rates for the major drug classes that are used for the treatment of therapy-naïve patients.
9. Mannheimer SB, Morse E, Matts JP, Andrews L, Child C, Schmetter B, Friedland GH: Sustained benefit from a long-term antiretroviral adherence intervention. Results of a large randomized clinical trial. J Acquir Immune Defic Syndr (2006) 43(Suppl 1):S41-S47.
10. Rockstroh J, Dejesus E, Donatacci L, Wat C, Bertasso A, Labriola-Tompkins E, Shikhman A, Atkins B, Guimaraes D, Wilkinson M, Thommes J et al: Adherence to enfuvirtide and its impact on treatment efficacy. AIDS Res Hum Retroviruses (2008) 24(2):141-148.
11. Beerenwinkel N, Däumer M, Sing T, Rahnenfuhrer J, Lengauer T, Selbig J, Hoffmann D, Kaiser R: Estimating HIV evolutionary pathways and the genetic barrier to drug resistance. J Infect Dis (2005) 191(11):1953-1960.
12. Struble K, Murray J, Cheng B, Gegeny T, Miller V, Gulick R: Antiretroviral therapies for treatment-experienced patients: Current status and research challenges. AIDS (2005) 19(8):747-756.
13. Smith CJ, Phillips AN, Hill T, Fisher M, Gazzard B, Porter K, Gilson R, Easterbrook P, Matthias R, Scullard G, Johnson MA et al: The rate of viral rebound after attainment of an HIV load < 50 copies/mL according to specific antiretroviral drugs in use: Results from a multicenter cohort study. J Infect Dis (2005) 192(8):1387-1397.
14. von Wyl V, Yerly S, Böni J, Bürgisser P, Klimkait T, Battegay M, Furrer H, Telenti A, Hirschel B, Vernazza PL, Bernasconi E et al: Emergence of HIV-1 drug resistance in previously untreated patients initiating combination antiretroviral treatment: A comparison of different regimen types. Arch Intern Med (2007) 167(16):1782-1790.
15. Boone L: Next-generation HIV-1 non-nucleoside reverse transcriptase inhibitors. Curr Opin Invest Drugs (2006) 7(2):128-135.
16. Zhang Z, Hamatake R, Hong Z: Clinical utility of current NNRTIs and perspectives of new agents in this class under development. Antivir Chem Chemother (2004) 15(3):121-134.
17. Silvestri R, Maga G: Current state-of-the-art in preclinical and clinical development of novel non-nucleoside HIV-1 reverse transcriptase inhibitors. Expert Opin Ther Pat (2006) 16(7):939-962.
18. Sahlberg C, Zhou X-X: Development of non-nucleoside reverse transcriptase inhibitors for anti-HIV therapy. Anti-Infective Agents Med Chem (2008) 7(2):101-117.
19. Beyer A, Lawtrakul L, Pungpo P, Wolschann P: Structural aspects of non-nucleoside HIV-1 reverse transcriptase inhibition. Curr Comput Aided Drug Des (2007) 3(2):87-100.
20. Sluis-Cremer N, Tachedjian G: Mechanisms of inhibition of HIV replication by non-nucleoside reverse transcriptase inhibitors. Virus Res (2008) 134(1-2):147-156. • Recent review of the multiple mechanisms by which NNRTIs can inhibit HIV replication.
21. Hang J, Li Y, Yang Y, Cammack N, Mirzadegan T, Klumpp K: Substrate-dependent inhibition or stimulation of HIV RNase H activity by non-nucleoside reverse transcriptase inhibitors (NNRTIs). Biochem Biophys Res Commun (2007) 352(2):341-350.
22. Vrouenraets SM, Wit FW, van Tongeren J, Lange JM: Efavirenz: A review. Expert Opin Pharmacother (2007) 8(6):851-871. • Provides a comprehensive review of the clinical profile of the currently preferred NNRTI efavirenz.
23. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents: Department of Health and Human Services, Washington, DC, USA (2008). www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
24. Knoll BM, Vento S, Temesgen Z: Etravirine. Drugs Today (Barc) (2008) 44(1):23-33.
25. Madruga JV, Cahn P, Grinsztejn B, Haubrich R, Lalezari J, Mills A, Pialoux G, Wilkin T, Peeters M, Vingerhoets J, de Smedt G et al: Efficacy and safety of TMC-125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet (2007) 370(9581):29-38. •• Provides, with reference [26••], the first proof-of-concept of NNRTI efficacy in patients for whom previous NNRTI-based therapies have failed.
26. Lazzarin A, Campbell T, Clotet B, Johnson M, Katlama C, Moll A, Towner W, Trottier B, Peeters M, Vingerhoets J, de Smedt G et al: Efficacy and safety of TMC-125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet (2007) 370(9581):39-48. •• Provides, with reference [25••], the first proof-of-concept of NNRTI efficacy in patients for whom previous NNRTI-based therapies have failed.
27. Wainberg MA: HIV resistance to nevirapine and other non-nucleoside reverse transcriptase inhibitors. J Acquir Immune Defic Syndr (2003) 34(Suppl 1):S2-S7.
28. Smith PF, DiCenzo R, Morse GD: Clinical pharmacokinetics of non-nucleoside reverse transcriptase inhibitors. Clin Pharmacokinet (2001) 40(12):893-905.
29. Rotger M, Tegude H, Colombo S, Cavassini M, Furrer H, Décosterd L, Blievernicht J, Saussele T, Günthard HF, Schwab M, Eichelbaum M et al: Predictive value of known and novel alleles of CYP2B6 for efavirenz plasma concentrations in HIV-infected individuals. Clin Pharmacol Ther (2007) 81(4):557-566.
30. Arendt G, de Nocker D, von Giesen HJ, Nolting T: Neuropsychiatric side effects of efavirenz therapy. Expert Opin Drug Saf (2007) 6(2):147-154.
31. Fumaz CR, Muñoz-Moreno JA, Moltó J, Negredo E, Ferrer MJ, Sirera G, Pérez-Alvarez N, Gómez G, Burger D, Clotet B: Long-term neuropsychiatric disorders on efavirenz-based approaches: Quality of life, psychologic issues, and adherence. J Acquir Immune Defic Syndr (2005) 38(5):560-565.
32. SUSTIVA® (efavirenz) capsules and tablets: Package insert, Bristol-Myers Squibb Co, Princeton, NJ, USA (2008). packageinserts. bms.com/pi/pi_sustiva.pdf
33. Fundarò C, Genovese O, Rendeli C, Tamburrini E, Salvaggio E: Myelomeningocele in a child with intrauterine exposure to efavirenz. AIDS (2002) 16(2):299-300.
34. Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989 to 31 July 2007. Antiretroviral Pregnancy Registry Steering Committee, Willmington, NC, USA (2007). www.apregistry.com/forms/ interim_report.pdf
35. Friis-Møller N, Reiss P, Sabin CA, Weber R, Monforte A, El-Sadr W, Thiébaut R, De Wit S, Kirk O, Fontas E, Law MG et al: Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med (2007) 356(17):1723-1735.
36. Podzamczer D, Olmo M, Sanz J, Boix V, Clotet B, Knobel H, Leibenger G, Domingo P, Pineda JA, Vilades C: Low hepatotoxicity in patients randomized to switching to nevirapine QD vs continuing with nevirapine BID. 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA (2008):960. www.retroconference.org/2008/PDFs/960.pdf
37. Markowitz M, Nguyen BY, Gotuzzo E, Mendo F, Ratanasuwan W, Kovacs C, Prada G, Morales-Ramirez JO, Crumpacker CS, Isaacs RD, Gilde LR et al: Rapid and durable antiretroviral effect of the HIV-1 integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: Results of a 48-week controlled study. J Acquir Immune Defic Syndr (2007) 46(2):125-133. • Demonstrates the comparable efficacy of the NNRTI efavirenz and the integrase inhibitor raltegravir after 48 weeks of combination therapy, suggesting a similar barrier to resistance for these two compounds.
38. Saag M, Ive P, Heera J, Tawadrous M, DeJesus E, Clumeck N, Cooper D, Horban A, Mohapi L, Mingrone H, Reyes-Teran G et al: A multicenter, randomized, double-blind, comparative trial of a novel CCR5 antagonist, maraviroc versus efavirenz, both in combination with Combivir (zidovudine [ZDV]/lamivudine [3TC]) for the treatment of antiretroviral-naïve subjects infected with R5 HIV-1: Week 48 results of the merit study. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Sydney, Australia (2007):WESS104. www.ias2007.org/pag/ppt/ WESS104.ppt
39. Riddler SA, Haubrich R, DiRenzo G, Peeples L, Powderly WG, Klingman KL, Garren KW, George T, Rooney JF, Brizz B, Havlir D et al: A prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infection - ACTG 5142. 16th International AIDS Conference, Montreal, Canada (2006):THLB0204.
40. Riddler SA, Haubrich R, DiRenzo G, Peeples L, Powderly WG, Klingman KL, Garren KW, George T, Rooney JF, Brizz B, Havlir D et al: Initial viral decay to assess the relative antiretroviral potency of PI-, NNRTI-, and NRTI-sparing regimens for first-line therapy of HIV-1 infection: ACTG 5160s (sub-study of ACTG 5142). 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA (2008):776.
41. Jülg B, Goebel FD: Clinical news from the XVI International AIDS Conference: The attempt of a summing up. Infection (2006) 34(5):294-297.
42. Braithwaite RS, Kozal MJ, Chang CC, Roberts MS, Fultz SL, Goetz MB, Gibert C, Rodriguez-Barradas M, Mole L, Justice AC: Adherence, virological and immunological outcomes for HIV-infected veterans starting combination antiretroviral therapies. AIDS (2007) 21(12):1579-1589.
43. Bartlett JA, Johnson J, Herrera G, Sosa N, Rodriguez A, Liao Q, Griffith S, Irlbeck D, Shaefer MS: Long-term results of initial therapy with abacavir and lamivudine combined with efavirenz, amprenavir/ritonavir, or stavudine. J Acquir Immune Defic Syndr (2006) 43(3):284-292.
44. Gulick RM, Ribaudo HJ, Shikuma CM, Lustgarten S, Squires KE, Meyer WA III, Acosta EP, Schackman BR, Pilcher CD, Murphy RL, Maher WE et al: Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med (2004) 350(18):1850-1861.
45. Sorbera LA, Serradell N, Rosa E, Bolós J: Rilpivirine: Reverse transcriptase inhibitor anti-HIV agent. Drugs Future (2007) 32(12):1046-1052.
46. Janssen PA, Lewi PJ, Arnold E, Daeyaert F, de Jonge M, Heeres J, Koymans L, Vinkers M, Guillemont J, Pasquier E, Kukla M et al: In search of a novel anti-HIV drug: Multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino] -2-pyrimidinyl]amino]benzonitrile (R-278474, rilpivirine). J Med Chem (2005) 48(6):1901-1909.
47. Das K, Bauman JD, Clark AD Jr, Frenkel YV, Lewi PJ, Shatkin AJ, Hughes SH, Arnold E: High-resolution structures of HIV-1 reverse transcriptase/TMC-278 complexes: Strategic flexibility explains potency against resistance mutations. Proc Natl Acad Sci USA (2008) 105(5):1466-1471. • Presents X-ray co-crystal structures of rilpivirine with wild-type and NNRTI-resistant proteins, which provide hypotheses for how next-generation NNRTIs may achieve a high genetic barrier to resistance.
48. Fang C, Bauman JD, Das K, Remorino A, Arnold E, Hochstrasser RM: Two-dimensional infrared spectra reveal relaxation of the non-nucleoside inhibitor TMC-278 complexed with HIV-1 reverse transcriptase. Proc Natl Acad Sci USA (2008) 105(5):1472-1477.
49. Hamatake R, Xu W, Raney A, Girardet JL, Nguyen M, Yeh LT, Quart B: An IQ assessment of RDEA806, a potent NNRTI with an excellent activity profile in the presence of human serum proteins. 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA (2008):731. www. retroconference.org/2008/PDFs/731.pdf
50. de Bethune MP, Andries K, Azijn H, Guillemont J, Heeres J, Vinderhoets J, Lewi P, Lee E, Timmerman P, Williams P: TMC278, a new potent NNRTI with an increased barrier to resistance and good pharmacokinetic profile. 12th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA (2005):556. www.retroconference.org/2005/cd/PDFs/556.pdf
51. Raney A, Hamatake R, Xu W, Vernier J-M, Girardet J-L, Weingarten P, Zhou D, Kim HK, Dick R, Yeh L-T, Quart B: RDEA427 and RDEA640 are novel NNRTIs with potent anti-HIV activity against NNRTI resistant viruses. 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA (2008):730. www.retroconference.org/2008/PDFs/730.pdf
52. Goebel F, Yakovlev A, Pozniak AL, Vinogradova E, Boogaerts G, Hoetelmans R, de Béthune MP, Peeters M, Woodfall B: Short-term antiviral activity of TMC-278 - a novel NNRTI - in treatment-naïve HIV-1-infected subjects. AIDS (2006) 20(13):1721-1726.
53. Yeni P, Goebel F, Thompson M, Vanveggel S, Peeters M, Stevens M, Williams P, Woodfall B, Boven K: TMC278, a next-generation NNRTI, demonstrates potent and sustained efficacy in antiretroviral (ARV)-naïve patients: Week 48 primary analysis of study TMC278-C204. 11th European AIDS Conference, Madrid, Spain (2007).
54. Mordant C, Schmitt B, Pasquier E, Demestre C, Queguiner L, Masungi C, Peeters A, Smeulders L, Bettens E, Hertogs K, Heeres J et al: Synthesis of novel diarylpyrimidine analogues of TMC-278 and their antiviral activity against HIV-1 wild-type and mutant strains. Eur J Med Chem (2007) 42(5):567-579.
55. Corbau R, Allan G, Burt C, Fishburn L, Irving S, Knoechel T, Macdonald G, Martin A, Mowbray C, Mori J, Panton W et al: UK-453,061: A non-nucleoside reverse transcriptase inhibitor of the treatment of drug-resistant HIV infections. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, USA (2007):F1-945.
56. Fätkenheuer G, Staszewski S, Plettenburg A, Hackman F, Layton G, McFadyen L, Davis J, Jenkins T. Short-term monotherapy with UK-453,061, a novel NNRTI, reduces viral load in HIV-infected patients. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Sydney, Australia (2007):WESS202.
57. Langdon G, Davis J, Layton G, Choo H, Ndongo M-N, Milton A, Vourvahis M: Pharmacokinetic interactions of the next-generation NNRTI UK-453,061 with other antiretrovirals and assessment of safety and tolerability in healthy male subjects. 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA (2008):763. www.retroconference.org/2008/ PDFs/763.pdf
58. Girardet J, Koh Y, De La Rosa M, Gunic E, Zhang Z, Hamatake RK, Yeh L: The discovery of RDEA806: A potent new HIV NNRTI in phase I clinical trials. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, USA (2007):H-1040.
59. Hamatake R, Zhang Z, Xu W, Girardet J, Quart B: RDEA806: A potent NNRTI with broad activity against resistant strains of HIV-1 and a high genetic barrier to resistance. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, USA (2007):H-1041
60. Zhang Z, Xu W, Koh YH, Shim JH, Girardet JL, Yeh LT, Hamatake RK, Hong Z: A novel nonnucleoside analogue that inhibits human immunodeficiency virus type 1 isolates resistant to current nonnucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother (2007) 51(2):429-437.
61. Yeh L, Ramael S, Comhaire S, Hingorani V, Manhard K, Nguyen M, Tieu K, Quart B: Safety and pharmacokinetics of ascending single oral doses of RDEA806, a novel HIV non-nucleoside reverse transcriptase inhibitor, in healthy volunteers. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, USA (2007):A-1429.
62. Ragno R, Artico M, De Martino G, La Regina G, Coluccia A, Di Pasquali A, Silvestri R: Docking and 3D QSAR studies on indolyl aryl sulfones. Binding mode exploration at the HIV-1 reverse transcriptase non-nucleoside binding site and design of highly active N-(2-hydroxyethyl)carboxamide and N-(2-hydroxyethyl)carbohydrazide derivatives. J Med Chem (2005) 48(1):213-223.
63. Richman D, Dousson C, Storer R, Moussa A, Randall J, Bridges E, Liuzzi M, Jakubik J, Seifer M, Standring D: IDX12899 and IDX12989, novel NNRTIs with potent anti-HIV activity, enhanced barrier to resistance and favorable pharmacokinetic profile. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, USA (2007):489.
64. Richman D, Jakubik J, Chapron C, Hubbard L, Gray L, Seifer M, Standring D: Genotypic resistance and phenotypic cross-resistance profile in vitro for a novel NNRTI: IDX899. 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA (2008):729. www.retroconference.org/2008/PDFs/729.pdf
65. Mayers D, Hard M, Damphousse D, Fielman B, Sullivan-Bolyai J, Belanger B, Zhou XJ: Dose escalation safety, tolerability, and pharmacokinetics of a novel HIV-1 NNRTI, IDX899 in healthy subjects. 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA (2008):764. www.retroconference.org/2008/PDFs/764.pdf
66. Idenix Pharmaceuticals Inc: IDX899 demonstrates rapid and profound inhibition of HIV replication in a phase I/II clinical trial in treatment-naïve HIV-infected patients. Press Release (2008) February 06.
67. Tucker TJ, Saggar S, Sisko JT, Tynebor RM, Felock PJ, Flynn JA, Lai M-T, Liang Y, Liu M, McGaughey G, Milleret MD et al: Discovery of MK-4965: A potent, orally bioavailable HIV-1 nonnucleoside reverse transcriptase inhibitor (NNRTI) with improved potency against key mutant viruses. 235th American Chemical Society National Meeting, New Orleans, LA, USA (2008):MEDI 174.
68. Vingerhoets J, Buelens A, Peeters M, Picchio G, Tambuyzer L, Van Marck H, De Smedt G, Woodfall B, de Béthune MP. Impact of baseline NNRTI mutations on the virological response to TMC125 in the phase III clinical trials DUET-1 and DUET-2. 16th International HIV Drug Resistance Workshop, Barbados, West Indies (2007).
69. Vingerhoets J, Azijn H, Fransen E, De Baere I, Smeulders L, Jochmans D, Andries K, Pauwels R, de Béthune MP: TMC125 displays a high genetic barrier to the development of resistance: Evidence from in vitro selection experiments. J Virol (2005) 79(20):12773-12782.
70. Su G, Paul A, Hang JQ, Harris S, Hogg H, Dunn J, Yan JM, Chow E, Cammack N, Klumpp K, Heilek G. In vitro selection and characterization of viruses resistant to R1206, a novel non-nucleoside reverse transcriptase inhibitor. 16th International HIV Drug Resistance Workshop, Barbados, West Indies (2007).
71. O'Meara JA, Jakalian A, LaPlante S, Bonneau PR, Coulombe R, Faucher AM, Guse I, Landry S, Racine J, Simoneau B, Thavonekham B et al: Scaffold hopping in the rational design of novel HIV-1 non-nucleoside reverse transcriptase inhibitors. Bioorg Med Chem Lett (2007) 17(12):3362-3366.
72. Muraglia E, Kinzel OD, Laufer R, Miller MD, Moyer G, Munshi V, Orvieto F, Palumbi MC, Pescatore G, Rowley M, Williams PD et al: Tetrazole thioacetanilides: Potent non-nucleoside inhibitors of WT HIV reverse transcriptase and its K103N mutant. Bioorg Med Chem Lett (2006) 16(10):2748-2752.
73. th International HIV Drug Resistance Workshop, Barbados, West Indies (2007).
74. Wang Z, Wu B, Kuhen KL, Bursulaya B, Nguyen TN, Nguyen DG, He Y: Synthesis and biological evaluations of sulfanyltriazoles as novel HIV-1 non-nucleoside reverse transcriptase inhibitors. Bioorg Med Chem Lett (2006) 16(16):4174-4177.
75. Williams TM, Ciccarone TM, MacTough SC, Rooney CS, Balani SK, Condra JH, Emini EA, Goldman ME, Greenlee WJ, Kauffman LR, O'Brien JA et al: 5-Chloro-3-(phenylsulfonyl)indole-2-carboxamide: A novel, non-nucleoside inhibitor of HIV-1 reverse transcriptase. J Med Chem (1993) 36(9):1291-1294.
76. Medina-Franco JL, Martínez-Mayorga K, Juárez-Gordiano C, Castillo R: Pyridin-2(1H)-ones: A promising class of HIV-1 non-nucleoside reverse transcriptase inhibitors. ChemMedChem (2007) 2(8):1141-1147.
77. Regina GL, Coluccia A, Piscitelli F, Bergamini A, Sinistro A, Cavazza A, Maga G, Samuele A, Zanoli S, Novellino E, Artico M et al: Indolyl aryl sulfones as HIV-1 non-nucleoside reverse transcriptase inhibitors: Role of two halogen atoms at the indole ring in developing new analogues with improved antiviral activity. J Med Chem (2007) 50(20):5034-5038.
78. Wolkenberg SE, Lu M, Munshi V, Moyer G, Feng M, Carella AV, Ecto LT, Gabryelski LJ, Lai MT, Prasad SG et al: Novel indole-3-sulfonamides as potent HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs). Bioorg Med Chem Lett (2008) 18(2):554-559.
79. Benjahad A, Oumouch S, Guillemont J, Pasquier E, Mabire D, Andries K, Nguyen CH, Grierson DS: Structure-activity relationship in the 3-iodo-4-phenoxypyridinone (IOPY) series: The nature of the C-3 substituent on anti-HIV activity. Bioorg Med Chem Lett (2007) 17(3):712-716.
80. Mugnaini C, Alongi M, Togninelli A, Gevariya H, Brizzi A, Manetti F, Bernardini C, Angeli L, Tafi A, Bellucci L, Corelli F et al: Dihydroalkylthio-benzyl-oxopyrimidines as inhibitors of reverse transcriptase: Synthesis and rationalization of the biological data on both wild-type enzyme and relevant clinical mutants. J Med Chem (2007) 50(26):6580-6595.
81. Mai A, Artico M, Rotili D, Tarantino D, Clotet-Codina I, Armand-Ugón M, Ragno R, Simeoni S, Sbardella G, Nawrozkij MB, Samuele A et al: Synthesis and biological properties of novel 2-aminopyrimidin-4(3H)-ones highly potent against HIV-1 mutant strains. J Med Chem (2007) 50(22):5412-5424.
82. Romines KR, Freeman GA, Schaller LT, Cowan JR, Gonzales SS, Tidwell JH, Andrews CW III, Stammers DK, Hazen RJ, Ferris RG, Short SA et al: Structure-activity relationship studies of novel benzophenones leading to the discovery of a potent, next generation HIV nonnucleoside reverse transcriptase inhibitor. J Med Chem (2006) 49(2):727-739.
83. Wu B, Kuhen K, Ngoc Nguyen T, Ellis D, Anaclerio B, He X, Yang K, Karanewsky D, Yin H, Wolff K, Bieza K et al: Synthesis and evaluation of N-aryl pyrrolidinones as novel anti-HIV-1 agents. Part 1. Bioorg Med Chem Lett (2006) 16(13):3430-3433.
84. Tucker TJ, Saggar S, Sisko JT, Tynebor RM, Felock PJ, Flynn JA, Lai MT, Liang Y, Liu M, Miller M, Moyer G et al: Design and synthesis of novel second generation HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs). 234th American Chemical Society National Meeting, Boston, MA, USA (2007):MEDI 457.
85. Dunn JP, Dunten P, Elworthy TR, Han X, Harris S, Heilek G, Hirschfeld DR, Hogg JH, Kaiser A, Kertesz DJ, Kim W et al: Discovery and optimization of diphenyl ether nonnucleoside inhibitors of HIV reverse transcriptase. 234th American Chemical Society National Meeting, Boston, MA, USA (2007):MEDI 458.
86. Klumpp K, Dunn J, Heilek G, Zhou A, Stefanidis D, Chen CW, Xu JB, Hang JQ, Martin M, Davidson J, Harris S et al: R1206, a representative of a new class of potent diphenylether non-nucleoside reverse transcriptase inhibitors broadly active against NNRTI resistant HIV-1 variants and achieving high systemic exposures and benign safety profiles in animal species. 16th International HIV Drug Resistance Workshop, Barbados, West Indies (2007).
87. Pozniak A, Steyn D, Grinazteijn B, Vinogradova E, Lupo S, Techasathit W, Vanveggel S, Peeters M, Gollav C, Williams P, Woodfall B, Boven K. Neuropsychiatric events with TMC278, an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI). 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Sydney, Australia (2007):WEPEA105. www.ias2007.org/pag/AbstractPlus/AbsDoc_4639_1.pdf
88. Merluzzi VJ, Hargrave KD, Labadia M, Grozinger K, Skoog M, Wu JC, Shih CK, Eckner K, Hattox S, Adams J et al: Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor. Science (1990) 250(4986):1411-1413.
89. th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA, (2005).
90. Rimsky LT, Tambuyzer L, Vinderhoets J, Azijn H, Staes M, Picchio G, Kraus G, de Béthune MP: Compilation of mutations associated with resistance to NNRTIs deduced from clinical samples, in vitro analyses and bibliographical studies. 16th International HIV Drug Resistance Workshop, Barbados, West Indies (2007).
91. De Clercq E: The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection. Antiviral Res (1998) 38(3):153-179.
92. Andries K, Azijn H, Thielemans T, Ludovici D, Kukla M, Heeres J, Janssen P, De Corte B, Vingerhoets J, Pauwels R, de Béthune MP: TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother (2004) 48(12):4680-4686.
93. GILEAD SCIENCES INC/KOREA RESEARCH INSTITUTE OF CHEMICAL TECHNOLOGY (Guo H, Kim CU, Kim HS, Lee C-K, Lee IY, Mitchell ML, Son JC, Xu L): Novel HIV reverse transcriptase inhibitors. WO-2008016522 (2008).
94. IRM LLC (Wu B, Nguyen TN, Ellis DA, He X, Anaclerio BM, Yang K, Choi H-S, Wang Z, Marsilje T, He Y) Phenyl-substituted pyrrolidones. WO-2006081554 (2006)
95. PFIZER LTD (Jones LH, Middleton DS, Mowbray CE, Newman SD, Williams DH) Chemical compounds. WO-2006067587 (2006).