Nonnucleoside inhibitor of HIV-1 reverse transcriptase

Non-competitive, allosteric inhibitors of adenosine kinase were reported by Butini et al.6S A biological screen of an in-house database of proprietary compounds identified pyrrolobenzoxazepines, representative of a class of nonnucleoside inhibitors of HIV-1 reverse transcriptase, with a unique T shape geometry as micromolar inhibitors of human adenosine kinase (e.g. compound... 

Grob PM, Wu JC, Cohen KA, et al. Nonnucleoside inhibitors of HIV-1 reverse transcriptase nevirapine as a prototype drug. AIDS Res Hum Retrovir 1992 8 145-152. 

Research on nonnucleoside inhibitors of HIV-1 reverse transcriptase from 4,5,6,7-tetrahydro-5-methylimidazo[4,5,l-/fc](l,4)benzodiazepin-2(lH)-one (TTBO) to etravirine (TMC125) 05JMC1689. 

R 61 J. Dornan, P. Taylor and M.D. Walkinshaw, Structures of Im-munophilins and Their Ligand Complexes , p. 1392 R 62 J.MJ. Tronchet and M. Seman, Nonnucleoside Inhibitors of HIV-1 Reverse Transcriptase From the Biology of Reverse Transcription to Molecular Design , p. 1496 Vol. 4, 2004... 

The chromeno-coumarin calanolide A, isolated from Calophyllum langiferum var. Austrocoriaceum, is nowadays in clinical trials as a nonnucleoside specific inhibitor of HIV-1 reverse transcriptase [64,65]. 

Schlabach AJ, Wolfgang JA, Condra JH. Functional analysis of HIV-1 reverse transcriptase amino acids involved in resistance to multiple nonnucleoside inhibitors. J Biol Chem 1992 267 17526-17530. 

Pharmacology Efavirenz is a nonnucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Its activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase (RT). It does not inhibit HIV-2 RT and human cellular DMA... 

Spence RA, Kati WM, Anderson KS, Johnson KA. Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors. Science 1995 267 988-993. 

Smith MBK, Rouzer CA, Taneyhill LA, Smith NA, Hughes SH, Boyer PL, et al. Molecular modeling studies of HIV-1 reverse transcriptase nonnucleoside inhibitors Total energy of complexation as a predictor of drug placement and activity. Protein Science 1995 4 2203-2222. 

Pata, J. D., Stirtan, W. G., Goldstein, S. W., and Steitz, T. A. (2004). Structure of HIV-1 reverse transcriptase bound to an inhibitor active against mutant reverse transcriptases resistant to other nonnucleoside inhibitors. Proc. Natl. Acad. Sri. USA 101, 10548-10553. 

Kleim JP, ROsner M, Winkler I, Paessens A, Kirsch R, Hsiou Y, Arnolds E, Riess G (1996) Selective pressure of a quinoxaline nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) on HIV-1 replication results in the emergence of nucleoside RT-inhibitor-specific (RT Leu-74 -> Val or He and Val-75 - > Leu or He) HIV-1 mutants, Proc Natl Acad Sci USA 93 34-38... 

The answer is f. (Kat urtg, p 837.) Havirenz is a specific inhibitor of HIV-1 viral growth. Its mechanism of action involves inhibition of nonnucleoside reverse transcriptase. 

Delavirdine mesylate is a member of the /7w(heteroaryl)piperazine (BHAP) class of nonnucleoside HIV-1 reverse transcriptase inhibitors (Adams et al., 1998 Romero et al., 1993 Romero, 1994). This class of compounds was discovered by Upjohn scientists from a computer-directed dissimilarity analysis of the Pharmacia Upjohn chemical library to select compounds for screening against HIV-1 RT. The result of the in vitro assay (Deibel et al., 1990) is an IC50 of 0.260 p,M, which is comparable to AZT. In accordance with the previous NNRTIs, delavirdine is a noncompetitive inhibitor of reverse transcriptase, and has a synergistic effect with nucleoside transcriptase and protease inhibitors (Chong et al., 1994). 

Mechanism of Action A nonnucleoside reverse transcriptase inhibitor that binds directly to HIV-1 reverse transcriptase, thus changing the shape of this enzyme and blocking RNA- and DNA-dependent polymerase activity. TherapeuticEffect Interferes with HIV replication, slowing the progression of HIV infection. 

Pyrrolopyridines substituted at the 2-position of dipyridodiazepinones have been prepared for study as nonnucleoside inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase <1997JME2430>. Compound 141, synthesized from pyrrolo[2,3-, ]pyridine as a starting material, has emerged as a novel inhibitor of HIV-1. Compound 141 acts by interfering with the initial viral entry process <2003JME4236>. 

Efavirenz is a nonnucleoside reverse transcriptase inhibitor specific for HIV-1. After binding to a site distant from the active site on the HIV-1 reverse transcriptase, it disrupts catalytic activity of the enzyme by causing a conformational change and does not compete with deoxynucleoside triphosphates. Efavirenz does not inhibit HIV-2 reverse transcriptase and human DNA polymerases a, (3, 7 and 8. The resistance to the drug develops rapidly from site-directed mutagenesis specifically at codon 103, and also at codons 100, 106, 108, 181, 190 and 225 of viral reverse transcriptase. This resistance will be applicable for all nonnucleoside transcriptase inhibitors. 

Delavirdine is a synthetic nonnucleoside reverse transcriptase inhibitor which after directly binding to HIV-1 reverse transcriptase blocks RNA-dependent and DNA-dependent DNA polymerase activities. It disrupts the catalytic activity of the enzyme after causing a conformational change in HIV-1 reverse transcriptase and does not... 

Fujihashi T, Hara H, Sakata T, Mori K, Higuchi H, Tanaka A, Kaji H, Kaji A (1995) Anti-Human Immunodeficiency Virus (HIV) Activities of Halogenated Gomisin J Derivatives, New Nonnucleoside Inhibitors of HIV Type 1 Reverse Transcriptase. Antimicrob Agents Chemother 39 2000... 

In seeking an efficient, economic, and scaleable route to the new potent nonnucleoside HIV-1 reverse transcriptase inhibitor 16 (L-738,372) [2a], process chemists at the Merck Research Laboratories have significantly contributed to the field of asymmetric alkylation of imines. Huffman and co-workers have reported a very efficient asymmetric route to 16 via the addition of a lithium acetylide to the cyclic N-acylketimine 14 in the presence of the lithium alkoxide of the alkaloid quinine as a stoichiometric chiral additive (Scheme 9) [31aj the previous route to the inhibitor 16 included a resolution step [31bj. Whereas other types of chiral additives were screened (e.g., diamines, diethers), only P-ami-no alkoxides were enantioselective. The search for readily available amino alcohols was dictated by the necessity of developing a practical process. The commer-... 

Mestres J, Rohrer DC, Maggiora GM. A molecular-field-based similarity study of nonnucleoside HIV-1 reverse transcriptase inhibitors. J Comput Aided-Mol Des 1999 13 79-93. 

Heterocycles as nonnucleoside reverse transcriptase inhibitors for therapy of HIV-1 infection 99F26. 

HIV infection In combination with other antiretroviral agents (such as nonnucleoside reverse transcriptase inhibitors or protease inhibitors) for the treatment of HIV-1 infection in adults. 

Merluzzi VJ, Hargrave KD, Labadia M, Grozinger K, Skoog M, Wu JC, et al. Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor. Science 1990 250 1411-1413. 

Vasudevachari MB, Battista C, Lane HC, Psallidopoulos MC, Zhao B, Cook J, et al. Prevention of the spread of HIV-1 infection with nonnucleoside reverse transcriptase inhibitors. Virology 1992 190 269-277. 

Albright AV, Erickson-Viitanen S, O Connor M, Frank I, Rayner MM, Gonzalez-Scarano F (2000) Efavirenz is a potent nonnucleoside reverse transcriptase inhibitor of HIV type 1 replication in microglia in vitro. AIDS Res Hum Retroviruses 16 1527-1537. 

Nevirapine is a nonnucleoside reverse-transcriptase inhibitor that inhibits replication of retroviruses, including HIV. In combination with other antiretroviral agents it is used for treatment of HIV-1 infection. 

Nevirapine (NVP), a nonnucleoside reverse transcriptase inhibitor, is widely used for the treatment of human immunodeficiency virus (HIV) infections. It is the main option for the first-line treatment of HIV-1, together with two nucleoside reverse transcriptase inhibitors, in countries with limited resources. NVP is associated with two serious clinically restrictive side effects skin reactions and hepatotoxicity. Severe, life threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis, and hepatic failure, has been reported in HIV-infected patients taking NVP (DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents 2008). For this reason, NVP is given a black box warning for hepatotoxicity, and concern has been raised over NVP-based treatment. 

Inhibition of human immunodeficiency vims type 1 reverse transcriptase by nucleosides such as AZT, DDC, DDI, D4T, and 3TC is a proven therapy for delaying the progression of AIDS. However, the rapid viral mutation to resistant strains requires the development of new therapeutic agents.The recent developments of both protease inhibitors and nonnucleoside reverse transcriptase inhibitors offer hope of effective treatment, especially when coadministered. " Efavirenz 290 is a nonnucleoside reverse transcriptase inhibitor that shows high potency against a variety of HIV-1 mutant strains. 

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