Elucidation of Novel 13-Series Resolvins that Increase with Atorvastatin and Clear Infections

Abstract

Endogenous mechanisms leading to host protection and resolution of infections without immunosuppression are of wide interest. Here we elucidated the structures of four new host-protective molecules produced in neutrophil-endothelial co-cultures, and present in human and mouse tissues after sterile inflammation or infection. These bioactive molecules contained conjugated triene and diene double bonds with each carrying a 13-carbon position alcohol and were derived from n-3 docosapentaenoic acid (DPA, C22:5). These compounds, termed 13-series resolvins (RvT), demonstrated potent protective actions increasing mice survival during Escherichia coli infections. RvT also regulated human and mouse phagocyte responses stimulating bacterial phagocytosis and regulating inflammasome components. Their biosynthesis during neutrophil-endothelial cell interactions was initiated by endothelial cyclooxygenase-2 (COX-2) and increased by atorvastatin via S-nitrosylation of COX-2. The actions of atorvastatin and RvT were additive in E. coli infections in mice where they accelerated resolution of inflammation and increased survival >60%.

1 . A compound having the formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein each of P 1 , P 2  and P 3 , when present, individually is a protecting group or a hydrogen atom; 
           , when present, represents a double bond and each double bond is independently in either the Z or the E configuration; 
         wherein the carbon at the 7 and 13 positions or 8, 12 or 20, when present, is independently in the R or S configuration; 
         Z is —C(O)OR d , —C(O)NR c R c , —C(O)H, —C(NH)NR c R c , —C(S)H, —C(S)OR d , —C(S)NR c R c , or —CN; 
         each R a , is independently selected from hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl or 6-16 membered heteroarylalkyl; 
         each R c , is independently a protecting group or R a , or, alternatively, each R c  is taken together with the nitrogen atom to which it is bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R a  or suitable R b  groups; 
         each R b  is independently selected from ═O, —OR d , (C1-C3) haloalkyloxy, —OCF 3 , ═S, —SR d , ═NR d , ═NOR d , —NR c R c , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R d , —S(O) 2 R d , —S(O) 2 OR d , —S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R d , —OS(O) 2 R d , —OS(O) 2 OR d , —OS(O) 2 NR c R c , —C(O)R d , —C(O)OR d , —C(O)NR c R c , —C(NH)NR c R c , —C(NR a )NR c R c , —C(NOH)R a , —C(NOH)NR c R c , —OC(O)R d , —OC(O)OR d , —OC(O)NR c R c , —OC(NH)NR c R c , —OC(NR a )NR c R c , —[NHC(O)] n R d , —[NR a C(O)] n R d , —[NHC(O)] n OR d , —[NR a C(O)] n OR d , —[NHC(O)] n NR c R c , —[NR a C(O)] n NR c R c R c , —[NHC(NH)] n NR c R c  or —[NR a C(NR a )] n NR c R c ; 
         each n, independently is an integer from 0 to 3; and 
         each R d , independently is a protecting group or R a ; or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein when Z is —C(O)OR d , then R d  for Z is not a hydrogen when P 1 , P 2  and/or P 3 , when present, are all hydrogen atoms. 
     
     
         3 . A purified compound of  claim 1 , wherein one or more of P 1 , P 2  and/or P 3 , are hydrogen atoms, Z is —C(O)OR d  and R d  of Z is a hydrogen atom. 
     
     
         4 . The compound of either of  claim 1 , wherein the compound is a pharmaceutically acceptable salt of the carboxylic acid. 
     
     
         5 . The compound of  claim 1 , further comprising a carrier to provide a composition. 
     
     
         6 . A method of treating or preventing inflammasome activation, diabetes, nasopharyngitis, arthralgia, diarrhea, pain in the extremities, bacterial infection, dyspepsia, nausea, musculoskeletal pain, muscle spasms, myalgia, insomnia, pharyngolaryngia pain, inflammation, tissue degeneration, arterial inflammation, arthritis, psoriasis, urticara, vasculitis, asthma, ocular inflammation, pulmonary inflammation, pulmonary fibrosis, seborrheic dermatitis, pustular dermatosis, cardiovascular diseases, recruitment of neutrophils, leukocytes and/or cytokines, allergy, Alzheimer's disease, asthma, atherosclerosis, cancer, cardiovascular diseases, diabetes, genitourinary disorders, hypertension, infectious diseases, neuromuscular disorders, renal disorders, oral infections or periodontal disease comprising the step of administering an effective amount of one or more of the compounds as claimed in  claim 1  to a subject in need thereof, such that the disease or condition is treated or prevented. 
     
     
         7 . A method to treat or prevent one or more of inflammasome activation, diabetes, nasopharyngitis, arthralgia, diarrhea, pain in the extremities, bacterial infection, dyspepsia, nausea, musculoskeletal pain, muscle spasms, myalgia, insomnia, pharyngolaryngia pain, inflammation, arterial inflammation, arthritis, psoriasis, urticara, vasculitis, asthma, ocular inflammation, pulmonary inflammation, pulmonary fibrosis, seborrheic dermatitis, pustular dermatosis, cardiovascular diseases, recruitment of neutrophils, leukocytes and/or cytokines, allergy, Alzheimer's disease, asthma, atherosclerosis, cancer, cardiovascular diseases, diabetes, genitourinary disorders, hypertension, infectious diseases, neuromuscular disorders, renal disorders, oral infections or periodontal disease comprising the step of administering an effective amount of one or more of compounds having the formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein each of P 1 , P 2  and/or P 3 , when present, individually is a protecting group or a hydrogen atom; 
           , when present, represents a double bond; and wherein each double bond is independently in the Z or the E configuration; 
         Z is —C(O)OR d , —C(O)NR c R c , —C(O)H, —C(NH)NR c R c , —C(S)H, —C(S)OR d , —C(S)NR c R c , or —CN; 
         each R a , is independently selected from hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl or 6-16 membered heteroarylalkyl; 
         each R c , is independently a protecting group or R a , or, alternatively, each R c  is taken together with the nitrogen atom to which it is bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R a  or suitable R b  groups; 
         each R b  is independently selected from ═O, —OR d , (C1-C3) haloalkyloxy, —OCF 3 , ═S, —SR d , ═NR d , ═NOR d , —NR c R c , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R d , —S(O) 2 R d , —S(O) 2 OR d , —S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R d , —OS(O) 2 R d , —OS(O) 2 OR d , —OS(O) 2 NR c R c , —C(O)R d , —C(O)OR d , —C(O)NR c R c , —C(NH)NR c R c , —C(NR a )NR c R c R c , —C(NOH)R a , —C(NOH)NR c R c , —OC(O)R d , —OC(O)OR d , —OC(O)NR c R c , —OC(NH)NR c R c , —OC(NR a )NR c R c , —[NHC(O)] n R d , —[NR a C(O)] n R d , —[NHC(O)] n OR d , —[NR a C(O)] n OR d , —[NHC(O)] n NR c R c , —[NR a C(O)] n NR c R c , —[NHC(NH)] n NR c R c  or —[NR a C(NR a )] n NR c R c ; 
         each n, independently is an integer from 0 to 3; and 
         each R d , independently is a protecting group or R a ; 
         or a pharmaceutically acceptable salt thereof, provided when Z is —C(O)OR d , then R d  for Z is not a hydrogen when P 1 , P 2  and P 3  are each hydrogen atoms, 
         to a subject in need thereof, such that the disease or condition is treated or prevented. 
       
     
     
         8 . The method of  claim 7 , wherein the compound is purified and when P 1 , P 2  and P 3  are hydrogen atoms, Z is —C(O)OR d  and R d  of Z is a hydrogen atom. 
     
     
         9 . The method of  claim 7 , wherein the compound is a pharmaceutically acceptable salt of the carboxylic acid. 
     
     
         10 . The method of  claim 7 , further comprising a carrier to provide a composition. 
     
     
         11 . A method to treat or prevent a bacterial infections comprising administering to a subject in need thereof a compound according to  claim 1  and a statin compound. 
     
     
         12 . A method to augment statin therapy comprising providing to a subject in need thereof a therapeutically effective amount of a compound according to  claim 1  in addition to a statin compound to a subject in need of statin therapy. 
     
     
         13 . A method to increase the survival rate of a subject suffering from bacterial infections comprising: administering to the subject a therapeutic amount of a compound according to  claim 1 . 
     
     
         14 . A method to promote phagocytosis, efferocytosis, wound healing and tissue regeneration in a subject in need thereof comprising, administering to a patient in need thereof a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         15 . A method of stimulating reactive oxygen species production in leukocytes comprising administering to a subject in need of leukocyte stimulation a therapeutic amount of a compound according to  claim 1 .