Inhibitors of geranylgeranyl-protein transferase
AssigneeMerck & Co., Inc.
InventorsJackson B. Gibbs, Samuel L. Graham
Life of this patent
Estimating the term…
Abstract
The compounds disclosed am analogs of the CAAX motif of proteins that can be modified by geranylgeranylation in vivo that selectively inhibit the geranylgeranylation of several proteins. The relatively poor activity of the compounds against the farnesyl protein transferase, which modifies several proteins important in cellular replication, allows the use of the compounds of the instant invention to treat diseases which which am regulated by the function of a geranylgeranylated protein, such as certain cancers and inflammatory diseases. Further contained in this invention are chemotherapeutic compositions containing these geranylgeranyl protein transfcrase type I inhibitors and methods for their production.
Claims10
A compound which inhibits geranylgeranyl protein transferase type I, and is a selectively more potent inhibitor of geranylgeranyl protein transferase than of farnesyl protein transferase, having the formula I:
- ##STR12## wherein:
- R.sup.1 and R.sup.2 are independently selected from:
- a) C.sub.2 -C.sub.8 alkyl;
- b) C.sub.2 -C.sub.8 alkenyl;
- c) C.sub.2 -C.sub.8 alkynyl;
- d) substituted C.sub.1 -C.sub.8 alkyl;
- e) aryl;
- f) substituted aryl;
- g) heteroaryl;
- h) substituted heteroaryl;
- and
- i) the side chain of a naturally occurring amino acid;
- R.sup.3 is selected from alkyl, alkenyl and alkynyl of 1 to 6 carbon atoms, either branched or straight chain, which is unsubstituted or substituted with a phenyl group;
- X--Y is ##STR13## and Z is H.sub.2 or O;
- or the pharmaceutically acceptable:
- salts thereof.
A compound which inhibits geranylgeranyl-protein transferase type I which is:
- N-(2(R)-amino-3-mercaptopropyl)-valyl-isoleucyl-leucine;
- N-(2(R)-amino-3-mercaptopropyl)-valyl-isoleucyl-leucine methyl ester;
- N-[5(S)-(2(R)-amino-3-mercaptopropylamino)-6(S)-methyl-2-(R)-isopropyl-3,4( E)-heptenoyl]-leucine;
- N-[5 (S)-(2(R)-amino-3 -mercaptopropylamino)-6(S)-methyl-2(R)-isopropyl-3,4(E)-heptenoyl]-leucine methyl ester;
- N-[2(S)-(2(S)-(2(R)-animo-3-mercaptopropylamino)-3(S)-methylpentyloxy)-3-me thylbutanoyl]-leucine;
- N-[2(S)-(2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyloxy)-3-me thylbutanoyl]-leucine methyl ester;
- or the pharmaceutically acceptable salts thereof.
Dependencies are inferred from the claim text.