HIV-1 attachment inhibitor

Wang T, Zhang Z, Wallace OB et al (2003) Discovery of 4-benzoyl-l-[(4-methoxy-lH- pyrrolo [2,3-b]pyridin-3-yl)oxoacetyl]-2-(R)-methylpiperazine (BMS-378806) a novel HIV-1 attachment inhibitor that interferes with CD4-gpl20 interactions. J Med Chem 46 4236-4239... 

Yang Z, Zadjura L, D Arienzo C et al (2005) Preclinical pharmacokinetics of a novel HIV-1 attachment inhibitor BMS-378806 and prediction of its human pharmacokinetics. Biopharm Drug Disp 26 387 -02... 

Yang Z, Zadjura LM, Marino AM et al (2010) Utilization of in vitro Caco-2 permeability and liver microsomal half-life screens in discovering BMS-488043, a novel HIV-1 attachment inhibitor with improved pharmacokinetic properties. J Pharm Sci 99 2135-2152... 

Hanna G, Lalezari J, Hellinger J et al (2004) Antiviral activity, safety, and tolerability of a novel, oral small-molecule HIV-1 attachment inhibitor, BMS-488043, in HIV-1 infected subjects. Abstract 141. 11th conference on retrovimses opportunistic infect, San Francisco, CA... 

Wang T, Ueda Y, Connolly TP et al (2010) Use of a phosphonoxymethyl prodrug approach to successfully improve the oral delivery of HIV-1 attachment inhibitors design, preclinical profile, and human exposure. Abstract MEDI-346. 239th ACS national meeting, San Francisco, CA... 

Kadow JF, Ueda Y, Meanwell NA et al (2012) Inhibitors of human immunodeficiency virus type 1 (HIV-1) attachment 6. Preclinical and human pharmacokinetic profiling of BMS-663749, a phosphonooxymethyl prodrug of the HIV-1 attachment Inhibitor 2-(4-ben-zoyl-l-piperazinyl)-l-(4,7-dimethoxy-lH-pyrrolor2,3-clpyridin-3-yl)-2-oxoethanone (BMS-488043). J Med Chem 55 2048-2056... 

Nettles R, Schurmann D, Zhu L et al (2012) Pharmacodynamics, safety, and pharmacokinetics of BMS-663068, an oral HIV-1 attachment inhibitor in HIV-1-infected subjects. J Inf Dis (manuscript accepted)... 

Nowicka-Sans B, Gong Y-f, Ho H-T et al (2011) Antiviral activity of a new small molecule HIV-1 attachment inhibitor, BMS-626529, the parent of BMS-663068. Poster 518. 118th conference retroviruses opportunistic infections, Boston, MA... 

Nowicka-Sans B, Gong Y-F, McAuliffe B et al (2012) In vitro antiviral characteristics of HIV-1 attachment inhibitor BMS-626529, the active component of the prodrug BMS-663068 (Manuscript in preparation)... 

Regueiro-Ren A, Xue QM, Ueda Y et al (2009) HIV-1 attachment inhibitors structure-activity relationships leading to the identification of l-(4-henzoylpiperazin-l-yl)-2-(4-fluoro-7-(l//-l,2,3-triazol-l-yl)-l//-pyrrolo[2,3-c]pyridin-3-yl)ethane-l,2-dione. Abstract MEDI-450. 238th ACS national meeting, Washington, DC... 

The 2-hydroxyethylene isostere is different from the 1-hydroxyethylene isostere only in the position of the hydroxy goup. In the 2-hydroxyethylene isostere the hydroxy group is attached to the C2 of ethylene, while it is on Cl in the 1-hydroxyethylene isostere. The 2-hydroxyethylene isostere has been applied to the design HIV-1 protease inhibitors.[51] However, the activity of the resulting compounds is lower than that of inhibitors in which the isostere is replaced with the 1-hydroxyethylene group. 

Independent molecular modeling studies of HIV-1 gpl20 inhibitors have appeared. The synthetic bivalent inhibitor 17, constructed from two molecules of 8 tethered at the C-4 positions, was reported [75]. However, the potency of this compound was not significantly enhanced when compared to 8 although it was more potent than a monomer core with the linker attached. 

Meanwell NA, Wallace OB, Fang H et al (2009) Inhibitors of HIV-1 attachment. Part 2 an initial survey of indole substitution patterns. Bioorg Med Chem Lett 19 1977-1981... 

Wang T, Yin Z, Zhang Z et al (2009) Inhibitors of human immunodeficiency virus type 1 (HIV-1) attachment. 5. An evolution from indole to azaindoles leading to the discovery of l-(4-benzoylpiperazin-l-yl)-2-(4,7-dimethoxy-l//-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-488043), a drug candidate that demonstrates antiviral activity in HIV-1-infected subjects. J Med Chem 52 7778-7787... 

Wang T. Inhibitors of Human Immunodeficiency Virus Type 1 (HIV-1) attachment. Part x. SAR of 4-Methoxy 6-Azaindole series of HIV gpl20 entry inhibitors and discovery of BMS-626529 and its phosphonoxymethyl prodrug BMS-663068 (Manuscript in preparation)... 

The substitution of phenyl ring with pyridine is widely used to improve metabolic stability. One efficient example of this can be recently found in HIV-1 inhibitors developed at Bristol-Myers Squibb and currently in clinical development. Compound 2 (Figure 2.5) was identified as lead in the discovery of drugs that inhibit the attachment of HIV to CD4 host cells but, due to high metabolism and low solubility, isosteres of the phenyl ring were evaluated. This led to the identification of BMS-488043 (Figure 2.5), which retained potency against HIV-1 attachment, but had better pharmacokinetic profile than compound 2 and was thus advanced in clinical trials [15]. 

The aldol reaction illustrated in eq 2 has been applied to the targeted synthesis of a number of complex molecules including Tylosin, Hapalosin, the antibiotic Sinefungin, and the HIV protease Saquinavir inhibitor. Oxazolidinone-type chiral auxiliaries derived from 1 have also been employed for the control of Diels-Alder reactions of attached acryloyl or crotonyl groups. ... 

Fig. 3 Amino acid residues in gpl20 predicted hy modeling to he near (9) and related attachment inhibitors. Dotted line represents a hydrogen bond between HIV-1 gpl20 and the inhibitor. Red amino acids (when appropriately mutated) reduce the binding affinity of one or more of the BMS inhibitors with HIV gpl20 (resistance mutations)...

A more sophisticated construct grafted N35 onto the amino terminus of a peptide comprised of N34 attached by a six-residue linker to C28 derived from HR-2 (N34-SGGRGG-C28) which adopts a stable, trimeric hairpin configuration in solution [122]. This peptide, designated NCCG-gp41, presents the N35 moiety in trimeric form and is a potent inhibitor of HIV-1 envelope-mediated cell-cell fusion, with an IC50 = 16.1 nM [122],... 

Kadow JF, Ueda Y, Connolly TP et al (2011) Discovery of BMS-663068, an HIV attachment inhibitor for the treatment of HIV-1. Abstracts MEDI-29. 241st ACS national meeting,... 

In this chapter, we hope to show how innovation was a key driver in discovering and developing the commercial synthesis of the complex API BMS-663068 (1), a potential first-in-class HIV attachment inhibitor prodrug, currently in clinical development (Figure 1). 

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