HIV/FIV protease inhibitors having a small P3 residue

Details HIV/FIV protease inhibitors having a small P3 residue HIV/FIV protease inhibitors having a small P3 residue

2000-06-08

2004-10-12

Russel, Jeffrey Edwin (Department: 1654)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S018700, C514S019300, C514S307000, C514S423000, C530S330000, C530S331000, C548S204000, C548S537000, C564S381000

Reexamination Certificate

active

06803466

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to HIV and FIV protease inhibitors. More particularly, the invention is directed to HIV and FIV protease inhibitors characterized by core structures having a small P3 residue. The invention is also directed to methods for making such compounds with clinically useful activity and which are potentially resistive against loss of inhibitory activity due to development of resistant strains of HIV.
BACKGROUND
The aspartyl protease (PR) of human immunodeficiency virus (HIV) has been the subject of extensive research for the development of therapeutically useful inhibitors to control the progression of human acquired immunodeficiency syndrome (AIDS). Four competitive inhibitors of this enzyme have been approved and several others are in clinical trials (Babine et al. Chem. Rev. 1997, 97, 1359-1472; De Lucca et al. Drug Discovery Today 1997, 2, 6-18; Vacca et al. Drug Discovery Today 1997, 2, 261-272; Huff et al. J. Med. Chem. 1991, 34, 2305; Wlodawer et al. Ann. Rev. Biochem. 1993, 62, 543-585). Despite the high potency and high selectivity of these inhibitors used in AIDS therapy, many drug-resistant variants of HIV have been identified, including 45 distinct drug-resistant variants found in the past 3 years.
The drug-resistant mutants are generated through incomplete suppression of the virus by inhibitors clinically and usually contain multiple substitutions in their proteases. Moreover, these mutant enzymes often exhibit cross-resistance to many structurally distinct protease inhibitors. Therefore, development of new broad-based protease inhibitors efficacious against a wide spectrum of HIV variants may be necessary in order to slow down the development of drug resistance (Schinazi et al. Int. Antiviral News 1997, 5, 129-142; Wilson et al. J. Biochim. Biophy. Acta 1997, 1339, 113-125; Erickson et al. Annu. Rev. Pharmacol. Toxicol. 1996, 36, 545-571; Gulnik et al. Biochemistry 1995, 34, 9282-9287; Erickson et al. Nature Struct. Biol. 1995, 2, 523-529; Condra et al. Nature, 1995, 374, 569-571; Otto et al. Proc. Natl. Acad. Sci. USA 1993, 90, 7543-7547; Wong et al. Science, 1997, 278, 1291-1295; Finzi et al. Science, 1997, 278, 1295-1300).
FIV is a retrovirus which causes an immunodeficiency syndrome in cats comparable to AIDS in humans (Talbott et al. Proc. Natl. Acad. Sci. USA 1989, 86, 5743-5747; Pedersen et al. Science 1987, 235, 790-793). Both HIV and FIV PRs are C2-symmetric homodimeric enzymes, and they have almost superimposable active-site structures that facilitate catalysis by an identical mechanism (Slee et al. J. Am. Chem. Soc. 1995, 117, 11867-11878). Similar to HIV PR, FIV PR also processes both structural proteins of gag and the enzymes encoded by pol during FIV replication (Kramer et al. Science 1986, 231, 1580-1584) Furthermore, six mutated residues in HIV PR causing drug resistance (K20I, V32I, I50V, N88D, L90M, Q92K; Mellors et al. Int. Antiviral News, 1995, 3, 8-13) are found in the structurally aligned native residues of FIV PR.
Kinetic studies have also demonstrated that various potent HIV PR inhibitors which interact with the binding region from S4 to S4′ are less efficient inhibitors of FIV PR by a factor of 100 or more and good inhibitiors of FIV PR are often better inhibitors of the wild-type and drug-resistant HIV PRs. In addition to the observation that FIV PR resembles many known drug-resistant HIV PRs, the cat offers a potential animal system to test the effectiveness of anti-lentiviral agents in vivo to speed up the drug development process.
What is needed are combinatorial libraries of HIV and FIV protease inhibitors and simple synthetic methods for making same.
Furthermore, what is needed is a class of HIV and FIV protease inhibitors having enhanced possibilities of variability at the binding region for improving binding between the enzyme and its inhibitor.
Finally, what is needed are new HIV and FIV protease inhibitors having clinically useful inhibitory activity and a resistivity to a loss of inhibitory activity due to development of resistant strains of HIV.
BRIEF SUMMARY OF THE INVENTION
One aspect of the invention is directed to a protease inhibitor represented by the following structure:
In the above structure, R
1
may be any of the following radicals: hydrogen, carbobenzyloxy-, carbobenzyloxy-valine-, carbobenzyloxy-glycine-valine-, carbobenzyloxy-alanine-valine-, carbobenzyloxy-leucine-valine-, carbobenzyloxy-phenylalanine-valine-, carbobenzyloxy-serine-valine-, carbobenzyloxy-alanine-asparagine-, carbobenzyloxy-threonine-valine- and carbobenzyloxy-valine-valine-. R
2
may be any of the following radicals: —CH
2
-Phenyl, and —CH
2
—CH(CH
3
)
2
. R
3
may be any of the following radicals: hydrogen, oxygen and hydroxyl; R
4
is selected from the group consisting of hydrogen, oxygen and hydroxyl, wherein R
3
and R
4
are not both hydroxyl and wherein R
3
and R
4
are either a single combined oxygen forming a carbonyl group. R
5
may be any of the following radicals: hydrogen, and oxygen; R
6
is selected from the group consisting of hydrogen, and oxygen, wherein R
5
and R
6
are either a single combined oxygen forming a carbonyl group or both seperately hydrogen. R
7
is a radical represented by the formula:
wherein R
8
is a radical selected from the group consisting of —(H)
2
, and —H(t-Butyl).
Another aspect of the invention is directed to a protease inhibitor represented by the following structure:
In the above structure, R
1
may be any of the following radicals: hydrogen, carbobenzyloxy-, carbobenzyloxy-valine-, carbobenzyloxy-glycine-valine-, carbobenzyloxy-alanine-valine-, carbobenzyloxy-leucine-valine-, carbobenzyloxy-phenylalanine-valine-, carbobenzyloxy-serine-valine-, carbobenzyloxy-threonine-valine-, carbobenzyloxy-alanine-asparagine- and carbobenzyloxy-valine-valine-. R
2
may be any of the following radicals: —CH
2
-Phenyl, and —CH
2
—CH(CH
3
)
2
. R
3
is either hydrogen or —OH.
Another aspect of the invention is directed to a protease inhibitor represented by the following structure:
In the above structure, R
1
may be any of the following radicals: hydrogen, carbobenzyloxy-, carbobenzyloxy-valine-, carbobenzyloxy-glycine-valine-, carbobenzyloxy-alanine-valine-, carbobenzyloxy-leucine-valine-, carbobenzyloxy-phenylalanine-valine-, carbobenzyloxy-serine-valine-, carbobenzyloxy-threonine-valine- , carbobenzyloxy-alanine-asparagine- and carbobenzyloxy-valine-valine-. R
2
is either —(H)
2
or —H(t-Butyl).
Another aspect of the invention is directed to a protease inhibitor represented by the following structure:
In the above structure, R
1
may be any of the following radicals: hydrogen, carbobenzyloxy-, carbobenzyloxy-valine-, carbobenzyloxy-glycine-valine-, carbobenzyloxy-alanine-valine-, carbobenzyloxy-leucine-valine-, carbobenzyloxy-phenylalanine-valine-, carbobenzyloxy-serine-valine-, carbobenzyloxy-threonine-valine-, carbobenzyloxy-valine-valine- and carbobenzyloxy-alanine-asparagine-.
Another aspect of the invention is directed to protease inhibitor represented by the following structure:
In the above structure, R
1
may be any of the following radicals: hydrogen, carbobenzyloxy-, carbobenzyloxy-valine-, carbobenzyloxy-glycine-valine-, carbobenzyloxy-alanine-valine-, carbobenzyloxy-leucine-valine-, carbobenzyloxy-phenylalanine-valine-, carbobenzyloxy-serine-valine-, carbobenzyloxy-threonine-valine-, carbobenzyloxy-valine-valine- and carbobenzyloxy-alanine-asparagine-.


REFERENCES:
patent: 5157041 (1992-10-01), Handa et al.
patent: 5294720 (1994-03-01), Jadhav et al.
patent: 5354866 (1994-10-01), Kempf et al.
patent: 5502060 (1996-03-01), Thompson et al.
patent: 5541321 (1996-07-01), Baker et al.
patent: 5552405 (1996-09-01), Gorys et al.
patent: 5567823 (1996-10-01), Tien et al.
patent: 5733906 (1998-03-01), Jungheim et al.
patent: 751145 (1997-01-01), None
patent: 92/00948 (1992-01-01), None
patent: 93/23361 (1993-11-01), None
patent: 97/21100 (1997-06-01), None
Dreyer et al. A Symmetric Inhibitor Binds HIV-1 Protease In Biochemistry. vol. 32, No. 3, pp. 937-947,

Affiliated with

Also associated with

Rating

HIV/FIV protease inhibitors having a small P3 residue does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with HIV/FIV protease inhibitors having a small P3 residue, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and HIV/FIV protease inhibitors having a small P3 residue will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3321284