Mevalonate pathway inhibitor as highly-efficient vaccine adjuvant

Abstract

Disclosed are inhibitors of mevalonate pathway as an efficient vaccine adjuvant and use thereof. In particular, the inhibitor is an acetoacetyl-CoA transferase inhibitor, a HMG-CoA synthase inhibitor, a HMG-CoA reductase inhibitor, a mevalonate kinase inhibitor, a phosphomevalonate kinase inhibitor, a mevalonate-5-pyrophosphate decarboxylase inhibitor, an isopentenyl pyrophosphate isomerase inhibitor, a farnesyl pyrophosphate synthase inhibitor, a geranylgeranyl pyrophosphate synthase inhibitor or a geranylgeranyl transferase (I, II) inhibitor. Also disclosed is an immunogenic composition comprising inhibitors of mevalonate pathway as an adjutant.

1 . An immunogenic composition comprising an adjuvant selected from the group consisting of:
 a farnesyl pyrophosphate synthase inhibitor;   a geranylgeranyl pyrophosphate synthase inhibitor;   a thiolase inhibitor;   a HMG-CoA synthase inhibitor;   a mevalonate kinase inhibitor;   a phosphomevalonate kinase inhibitor;   a mevalonate-5-pyrophosphate decarboxylase inhibitor;   an isopentenyl pyrophosphate isomerase inhibitor; and   a geranylgeranyl transferase (I, II) inhibitor.   
     
     
         2 . The immunogenic composition of  claim 1 , wherein the farnesyl pyrophosphate synthase inhibitor is a bisphosphonic acid compound or a pharmaceutically acceptable salt, ester, prodrug, or solvate thereof. 
     
     
         3 . The immunogenic composition of  claim 2 , wherein the bisphosphonic acid compound is selected from the group consisting of zoledronic acid, pamidronic acid, alendronic acid, ibandronic acid, neridronic acid, risedronic acid, olpadronic acid, and minodronic acid, or a pharmaceutically acceptable salt, ester, prodrug, or solvate thereof. 
     
     
         4 . The immunogenic composition of  claim 1 , wherein the farnesyl pyrophosphate synthase inhibitor is a compound of the following Formula or a pharmaceutically acceptable salt, ester, prodrug, or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, alkylthio, halogen, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl group in said alkoxy group is optionally substituted with aryl, heteroaryl or heterocyclyl, wherein said aryl, heteroaryl or heterocyclyl is optionally substituted with alkyl or carbamoyl; 
         R 2  is selected from the group consisting of hydrogen, alkyl, alkoxy, alkylamino, alkylthio, halogen, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; 
         R 3  is selected from the group consisting of hydrogen, alkyl, alkoxy, alkylamino, alkylthio, halogen, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; 
         or R 2  and R 3  together with the carbon atom to which they are attached form an aromatic or heteroaromatic ring; and 
         R 4  is selected from the group consisting of hydrogen, alkyl, alkoxy, alkylamino, alkylthio, halogen, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; 
         or 
         the farnesyl pyrophosphate synthase inhibitor is a compound of the following Formula or a pharmaceutically acceptable salt, ester, prodrug, or solvate thereof: 
       
       
         
           
           
               
               
           
         
         wherein: 
         R 5  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, alkylthio, halogen, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; 
         R 6  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, alkylthio, halogen, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; 
         R 7  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, alkylthio, halogen, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; and 
         R 8  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, alkylthio, halogen, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl. 
       
     
     
         5 . The immunogenic composition of  claim 1 , wherein the adjuvant is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         6 . The immunogenic composition according to  claim 1 , comprising one or more antigens. 
     
     
         7 . The immunogenic composition according to  claim 1 , further comprising another adjuvant. 
     
     
         8 . The immunogenic composition according to  claim 1 , suitable for immunization by oral, topical or parenteral route. 
     
     
         9 . Use of the immunogenic composition according to  claim 1  in the preparation of the following vaccines: BCG vaccine, hepatitis A vaccine, hepatitis B vaccine, hepatitis C vaccine, hepatitis D vaccine, hepatitis E vaccine, influenza vaccine, polio vaccine, DPT vaccine, measles vaccine,  vaccinum  encephalitidis epidemicae, rabies vaccine, hemorrhage fever vaccine, pneumonia vaccine, epidemic menigitis vaccine, hepatitis A vaccine, mumps vaccine, influenza vaccine, rubella vaccine, varicella vaccine, AIDS vaccine, malaria vaccine, and vaccines for the treatment and prevention of cancers, including but not limited to melanoma therapeutic vaccines, melanoma prophylactic vaccines, lung cancer therapeutic vaccines, lung cancer prophylactic vaccines, bladder cancer prophylactic vaccines, bladder cancer therapeutic and prophylactic vaccines, cervical cancer therapeutic vaccines, cervical cancer prophylactic vaccines, bladder cancer therapeutic vaccines, bladder cancer prophylactic vaccines, breast cancer therapeutic vaccines, breast cancer prophylactic vaccines, liver cancer therapeutic vaccines, liver cancer prophylactic vaccines, prostate cancer therapeutic vaccines, and prostate cancer prophylactic vaccines. 
     
     
         10 . A compound of following Formula, or pharmaceutically acceptable salt, ester, prodrug, or solvate thereof, 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of alkenyl, alkynyl, alkoxy, alkylamino, alkylthio, hydroxy, and cycloalkyl, wherein the alkyl group in said alkoxy group is optionally substituted with aryl, heteroaryl or heterocyclyl, wherein said aryl, heteroaryl or heterocyclyl is optionally substituted with alkyl or carbamoyl; 
         R 2  is selected from the group consisting of hydrogen, alkyl, alkoxy, alkylamino, alkylthio, halogen, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; 
         R 3  is selected from the group consisting of hydrogen, alkyl, alkoxy, alkylamino, alkylthio, halogen, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; 
         or R 2  and R 3  together with the carbon atom to which they are attached form an aromatic or heteroaromatic ring; and 
         R 4  is selected from the group consisting of hydrogen, alkyl, alkoxy, alkylamino, alkylthio, halogen, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl. 
       
     
     
         11 . A compound of following Formula, or pharmaceutically acceptable salt, ester, prodrug, or solvate thereof, 
       
         
           
           
               
               
           
         
         wherein: 
         R 5  is selected from the group consisting of alkenyl, alkynyl, alkoxy, alkylamino, alkylthio, halogen, hydroxy, and cycloalkyl; 
         R 6  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, alkylthio, halogen, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; 
         R 7  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, alkylthio, halogen, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; and 
         R 8  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, alkylthio, halogen, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl. 
       
     
     
         12 . The compound of  claim 10 , wherein the compound is one of the following Formulae, or pharmaceutically acceptable salt, ester, prodrug, or solvate thereof,