HIV 1 protease inhibitor

Inhibitors of viral protease prevent cleavage of inactive precursor proteins, and hence viral maturation. They are administered orally. 

Saquinavir could be considered an abnormal peptide. Its bioavailability is low. Ritonavir, indinavir, nelfinavir, and amprena- 

K[ (IC50), nM Antiviral activity IC50 (IC90), nM Reference 

These compounds showed much improved activity against pro-tease-resistant strains of HIV as compared with DMP450. Both 8 and 9 exhibited good oral bioavailability (60%) and a sustained plasma half-life (3-8 hours). One additional advantage of the nonsymmetrical inhibitors was their reduced molecular weight compared with polar symmetrical inhibitors. Plasma levels of cyclic ureas dropped abrupdy when the molecular weight of a compound exceeded 620 Da. 

The symmetrical seven-membered sulfone, 11 (Table I), has been reported by Kim to show high in vitro potency (IC50 = 1 nM), good antiviral activity in cell culture (EC90 = 20 nJM), and excellent pharma- 

Inhibitor Identification through Broad-Based Screening 

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Flow chart showing the design of novel orally active HIV-1 protease inhibitor. (Figure adapted from Lam P K ]adhav, C E Eyermann, C N Hodge, Y Ru, L T Bacheler, ] L Meek, M ] Otto, M M Rayner, Y N V /ong, ang, P C Weber, D A Jackson, T R Sharpe and S Erickson-Viitanen 1994. Rational Design of Potent, able. Nonpeptide Cyclic Ureas as HIV Protease Inhibitors. Science 263 380-384.)... 

A Scheme for the preparation of a series of eyelie urea HIV protease inhibitors eontaining alkynyl-tethered heteroeyeles in the P2 region ineludes hydrogenation with LiAlH4 in THF in 60-80% yields (96BMCL797) (Sehemes 83 and 84). 

Uiastereoselecdve catalydc nitro-aldol reacdons of opdcally acdve iV-phthaloyl-c-phenyl-alanal with nitromethanein the presence of LLB proceed with high diastereoselecdvityfruirdryii = 99 11 as shown in Eq. 3.76. The product is converted via the Nef teacdon into f3S,35 -3-amino-3-hydroxy-4-phenylbutanoic acid, which is a subunit of the HIV-protease inhibitor... 

The Henry reactions of A, ALdibenzyl-L-phenylalaninal with nitroalkanes using 1.2 equiv of tetrabutylammonium fluoride (TBAF) as the catalyst proceed in ahighly stereoselective manner, as shown in Eqs. 3.82 and 3.83. This reaction provides rapid and stereoselective access to important molecules containing 1,3-diamino-2-hydroxypropyl segments, which are cenhal structural subunit of the HIV protease inhibitor amprenavir (in Scheme 3.21). 

Saquinavir was the fust HIV protease inhibitor to obtain FDA approval in 1995 for the treatment of HIV infection... 

Nelfinavir is a nonpeptidic, rationally designed HIV protease inhibitor. Nelfinavir has demonstrated efficacy in both monotherapy and in combination with the reverse transcriptase inhibitors stavudine (d4T) or zivudine + 3TC. The major side effect is mild to moderate diarrhea. 

Amprenavir (APV, Agenerase) is the most recently approved HIV protease inhibitor. It is smaller and stereochemically less complex than the other drugs in this class. Adsorption of this compound was found to be impaired by high fat meals. Common side effects of Amprenavir are nausea, vomiting, diarrhea, rash and a tingling sensation around the mouth. 

As with reverse transcriptase inhibitors, resistance to protease inhibitors may also occur. Mutations in the HIV protease gene were shown to confer resistance to each of the aforementioned molecules. In addition, passaging of viius in the presence of HIV protease inhibitors also gave rise to strains less susceptible to the original inhibitor or cross-reactive to other compounds in the same class. New Diug Targets... 

Tavel JA (2000) Ongoing trials in HIV protease inhibitors. Exp Opin Invest Drugs 9 917-928... 

Jones K, Hoggard PC, Khoo S, Maher B, Back DJ (2001) Effect of alphal-acid glycoprotein on the intracellular accumulation of the HIV protease inhibitors saquinavir, ritonavir and indinavir in vitro, Br J Chn Pharmacol 51 99-102... 

Moyle GJ, Back D (2001) Principles and practice of HIV-protease inhibitor pharmacoenhance-ment. HIV Med 2 105-113... 

Chellappan S, Kiran Kumar Reddy GS, All A, Nalam MN, Anjum SG, Cao H, Kairys V, Fernandes MX, Altman MD, Tidor B, Rana TM, Schiffer CA, Gilson MK (2007) Design of mutation-resistant HIV protease inhibitors with the substrate envelope hypothesis. Chem Biol Drug Des 69 455... 

Stein DS, Fish DG, Bilello JA, Preston SL, Martineau GL, Drusano GL (1996) A 24-week open-label phase I/II evaluation of the HIV protease inhibitor MK-639 (indinavir). AIDS 10 485 92... 

Thaisrivongs S, Strohbach JW (1999) Structure-based discovery of Tipranavir disodium (PNU-140690E) a potent, orally bioavadable, nonpeptidic HIV protease inhibitor. Biopolymers 51 51-58... 

This type of analysis is now well established and has been used in many drug discovery projects over the past fifteen years. Examples include HIV protease inhibitors [13], anti-influenza drugs [14], isoform-selective ligands for the estrogen receptor [15], and many more. 

Lam PYS, Jadhav PK, Eyermann CJ, Hodge CN, Ru Y, Bacheler LT, Meek JL, Otto MJ, Rayner MM, Wong YN, Chang CH, Weber PC, Jackson DA, Sharpe TR, Erickson-Viitanen S. Rational design of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors. Science 1994 263 380-4. 

De Lucca GV, Erickson-Viitanen S, Lam PYS. Cyclic HIV protease inhibitors capable of displacing the active site strnctnral water molecule. Drug Discov Today 1997 2 6-18. 

Polli JW, Jarrett JL, Studenberg SD, Humphreys JE, Dennis SW, Brouwer KR, et al. Role of P-glycoprotein on the CNS disposition of amprenavir (141W94), an HIV protease inhibitor. Pharm Res 1999 16 1206-12. 

Reverse transcriptase inhibitors prevent DNA from being produced in newly infected cells. They do not, however, prevent the reactivation of HIV from previously infected cells, the reason being that the enzyme is not involved in this process. Thus, agents that act at a later point in the replication cycle, possibly preventing reactivation, would be a major advance in the treatment of AIDs sufferers. The HIV protease inhibitors, which are currently receiving considerable attention, are believed to act in the manner depicted in Fig. 5.24. 

Gambari R, Lampronti I, Bianchi N, Zuccato C, Viola G, Vedaldi D, Dall Acqua F (2007) Structure and Biological Activity of Furocoumarins. 9 265-276 Garg R, Bhhatarai B (2006) QSAR and Molecular Modeling Studies of HIV Protease Inhibitors. 3 181-272... 

Davies and Reider (1996) have given some details of the HIV protease inhibitor CRDCIVAN (INDINAVIR) for which (lS,2R)-c -amino indanol is required. Indene is epoxidized enantioselectively, using the lacobsen strategy (SS-salen Mn catalyst, aqueous NaOH and PiNO), to (lS,2/ )-indene oxide in a two-phase system, in which the OH concentration is controlled. Indene oxide was subjected to the Ritter reaction with MeCN, in the presence of oleum, and subsequent hydrolysis and crystallization in the presence of tartaric acid gives the desired amino indanol. 

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