Modulators of cysteine protease

Details Modulators of cysteine protease Modulators of cysteine protease

2000-10-23

2004-12-07

Wang, Shengjun (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C514S622000, C514S617000, C514S678000, C514S676000

Reexamination Certificate

active

06828350

ABSTRACT:

FIELD OF THE INVENTION
The present invention concerns novel pharmaceutical compositions. In particular, the pharmaceutical compositions of the invention comprise cysteine protease modulators. The pharmaceutical compositions of the invention are preferably used for the treatment of viral infections, and diseases resulting from inappropriate apoptosis.
BACKGROUND OF THE INVENTION
Cysteine proteases are a major family of peptide-bond-cleaving hydrolases, defined as proteases in which the thiol group of a cysteinee residue serves as nucleophile in a catalysis. All known cysteinee peptidases require a second residue—an adjacent histidine—for catalysis. While the role of the histidine has been postulated to be a general base in analogy to well-understood serine proteases, it has been clearly demonstrated in theoretical studies that the catalytic histidine cannot act as a base, rather that it acts by donating a proton to the substrate. Cysteinee proteases have been found in the previous literature in viruses, bacterial protozoa, plants, mammals and fungi.
There are currently known 38 families of cysteinee proteases (C1-C38), most of which are divided into 5 separately evolved clans (CA-CE). Clan CB enzymes are chymotrypsin-like cysteine proteases containing a His/Cys diad (catalytic histidine preceding catalytic cysteinee in the linear sequence), and responsible for proteolytic cleavage of pol polyproteins (containing the RNA polymerase). These enzymes, commonly hydrolyse glutaminyl bonds, and act on crucial cell proteins as additional substrates.
Peptidases of Clan CA include vital mammalian enzymes such as papain or cathepsins. The normal activity of these enzymes is essential and their activity should not be inhibited by any type of pharmaceutical composition.
Clan CC includes sixteen (16) families of papain-like viral peptidases (C6-C9,C16,C21,C23,C27-29,C31-C36), comprising a cys/his diad. Despite sequences similar to Clan CA enzymes, these viral proteins are functionally similar to Clan CB enzymes, which cleave viral polyproteins.
Clan CD is represented by a single family (C14), which comprises cytosolic endopeptidases found only in animals. Cytosolic endopeptidases are involved in the process of apoptosis (programmed cell death).
There is no structural data regarding peptidases of Clan CE (family C5 adenovirus endopeptidase), as well as untyped enzymes. One untyped family, however, C13, which includes medically important proteases such as
Schistosoma mansoni
haeomoglobinase, is similar to the substrate specificity of Clan CB enzymes (asparaginyl compared to glutaminyl bonds). Additionally, C13 has a low sensitivity to E64. Interestingly, this latter property may indicate a fold similar to Clan CB chymotrypsin-like-enzymes.
Picornaviruses are single-stranded positive RNA viruses that are encapsulated in a protein capsid. These viruses cause a wide range of diseases in man and animal including common cold, poliomyelitis, hepatitis A, encephalitis, meningitis and foot-and-mouth disease, as well as diseases in plants such as the potty disease in potatoes. After inclusion into the host cell, the picornaviral RNA is translated into a 247-kDa protein that is co- and post-translationally cleaved yielding eleven (11) mature proteins. Cysteine proteases denoted 2A and 3C, which are part of the picornaviral self polyprotein are responsible for these cleavages. The 2A protease cleaves co-translationally between the structural and non-structural proteins and the 3C protease cleaves post-translationally the remaining cleavage sites except one.
Having been recognized as important proteins in the maturation of the picornaviral life cycle the 3C and 2A proteases have been a prime target for extensive structural and mechanistic investigations during the last few years. Recently, their mechanism and structural features have been determined (Kreisberg et al,
Organic Reactivity: Physical and Biological Aspects,
110-122 (1995)).
Site-directed mutagenesis studies (Cheah K. C. et al,
J. Biol. Chem.,
265 (13):7187-7189 (1990)) confirmed by X-ray studies (Matthews et al,
Cell,
77:761-771, (1994)) led to the finding that the catalytic site of 3C is composed of the following amino acids: Cys in position 146, Glu/Asp in position 71 and His in position 40. These three amino acids in the catalytic site of the 3C enzyme constitute a hybrid between the amino acids at the catalytic site of cysteine proteases and serine proteases.
The 3C protease has been shown by mutagenesis and crystallography to depend on a his/cys diad (His40, Cys146—rhinovirus numbering). A third conserved residue in the 3C protease, Asp 71, was initially considered analogous to Asn175 (the third member in the catalytic triad of papain), however crystallography has shown this residue to be of minor catalytic importance.
Due to the involvement of various cysteine proteases in many disorders and diseases ranging from microorganism infection (viral and bacterial) to inflammatory and tumor processes, there have been recently many attempts to find inhibitors for cysteine proteases (Otto and Schimeister,
Chem. Rev.,
97:133-171, 1997)).
There have also been attempts to find suitable inhibitors of the picornavirus 3C and 2A proteases in order to treat viral infections. By inhibiting these proteases, the production of new virions can be avoided because there are no native cellular proteases that can replace the cleavage activity of the viral proteases. Therefore, finding an efficient inhibitor against 3C and/or 2A picornavirus proteases will lead to the production of an anti-viral pharmaceutical composition against a large number of viral diseases occurring both in man and in animal.
The first agent found as an inhibitor of the 3C protease is Thysanone, an antibiotic compound obtained from
Thysanophora peniciloides
(Singh et al,
Tetrahedron Lett.,
32:5279-82 (1991)). However, this compound was not developed into a pharmaceutical composition because it was found to be an efficient inhibitor of the enzyme elastase present in erythrocytes.
Two additional antibiotic compounds of fungal origin, citrinin hydrate and radicinin, were obtained by screening microbial extracts (Kadam et al,
J. Antibiotics
7:836-839 (1994)). These novel two compounds showed a lower level of inhibition than thysanone. The same year a new compound termed kalafungin, which is also an antibiotic compound, was discovered by structural comparison to radicinin. Kalafungin was found to be a better inhibitor (by three orders of magnitude) than radicinin and citrinin hydrate (McCall et al,
Biotechology,
12:1012-1016 (1994)).
Another group of inhibitors, substituted isatins, has also been examined (S. E. Webber, et al.,
Med. Chem.,
39:5072-5082, 1996). Certain members of this group show significant inhibition of 3C proteases with concentrations in the nanomolar range, but are highly toxic. Other members of the group are relatively non-toxic, but have poor antiviral activity. It has recently been shown that peptidyl Michael acceptors inhibit rhinovirus replication at low micromolar concentrations with a therapeutic index exceeding ten (10) (Kong et al.,
J. Med. Chem.,
41:2579-2587 (1998). Rhinovirus inhibition has also been accomplished at nanomolar concentrations at peptidyl Michael acceptors (Dragovich et al.,
J. Med. Chem.,
41:2819-2834 (1998)). Thus, none of the above inhibitors has been demonstrated to be clinically useful possessing a sufficiently high therapeutic index with favorable toxicology and bioavailability profiles.
Transition-state analogs are well established as enzyme and protease inhibitors (Barrett, A. J. and Salvesen, G.,
Proteinase Inhibitors,
Elsevier, 1986). Functional groups such as ketone, aldehyde, chloromethyl-ketone (REVS) and recently isatin are widely used for the inhibition of serine and cysteine proteases. Class-specificity is achieved by utilization of phosphine or boron geometries (serine proteases) or groups such as epoxide (Albeck, M., Fluss, S. and Persky, R.,
J. Am. Chem. Soc.,
118:3591-3596, 1996), cyclopropenone (Ando,

Affiliated with

Also associated with

Rating

Modulators of cysteine protease does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Modulators of cysteine protease, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Modulators of cysteine protease will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3323659