Arginase inhibitors and methods of use

Abstract

The present invention is directed to arginase inhibitor compounds of formula IA or formula IB: or a pharmaceutically acceptable salt thereof, compositions containing these compounds, and methods of their use for the treatment and diagnosis of conditions characterized by upregulation of arginase, abnormally high arginase activity, or by abnormally low nitric oxide synthase activity.

1 . A compound of formula IA or formula IB: 
       
         
           
           
               
               
           
         
         or a stereoisomer, lactone prodrug, or pharmaceutically-acceptable salt thereof; 
         wherein: 
         said dashed line represents an optional double bond; 
         Z is 
       
       
         
           
           
               
               
           
         
         X 1  is —(CH 2 )— or, when said double bond is present between X 1  and X 2 , X 1  is —(CH)—; 
         X 2  is —(CH 2 )— or —(NR 2 )—, or, when said double bond is present between X 1  and X 2  or between X 2  and X 3 , X 2  is —(CH)— or N; 
         X 3  is —(CH 2 )—, a heteroatom moiety selected from the group consisting of —S—, —O— and —(NR 2 )— or, when said double bond is present between X 2  and X 3  or between X 3  and X 4 , X 3  is —(CH)— or N; 
         X 4  is —(CH 2 )— or, when said double bond is present between X 3  and X 4 , X 4  is —(CH)— and is in the trans configuration; 
         provided that not more than one of X 2  and X 3  is said —(NR 2 )— or said heteroatom moiety; 
         provided that X 3  is —(NR 2 )— when Z is 
       
       
         
           
           
               
               
           
         
         provided that there are no more than two double bonds between X 1 , X 2 , X 3 , and X 4  and no two double bonds share a common carbon atom; 
         R 1  is a monovalent moiety other than H; or R 1  and said α-carboxylate, when taken together, form a lactone; and 
         R 2  is, independently, H, methyl, or ethyl. 
       
     
     
         2 . The compound according to  claim 1 ,
 wherein said compound has L-stereochemistry and   wherein said compound has the structure (formula Ia) below:   
       
         
           
           
               
               
           
         
       
       and
 wherein said compound has the structure (formula Ib) below: 
 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound according to  claim 1 , wherein:
 R 1  is (C 1 -C 20 )alkyl, hydroxy(C 1 -C 20 )alkyl, hydroxy(C 2 -C 20 )alkenyl, (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, (C 5 -C 50 )aryl, (C 3 -C 50 )heteroaryl having at least one heteroatom selected from N, O, and S; (C 5 -C 50 )aryl(C 1 -C 20 )alkyl, (C 3 -C 50 )heteroaryl(C 1 -C 20 )alkyl, (C 2 -C 50 )heterocycloalkyl(C 1 -C 20 )alkyl, (C 5 -C 50 )aryloxy(C 1 -C 20 )alkyl, (C 5 -C 50 )arylthio(C 1 -C 20 )alkyl, (C 3 -C 50 )heteroaryloxy(C 1 -C 20 )alkyl, (C 5 -C 50 )arylamino(C 1 -C 20 )alkyl, (C 3 -C 50 )heteroarylamino(C 1 -C 20 )alkyl, amino(C 1 -C 20 )alkyl, —R x —C(═O)—R y , —R x —O—R z , —R x —O—R x —NR 3 R 5 , —R x —NR 3 R 5 , —R x —O—C(═O)—R y , (C 1 -C 6 )alkyl-B—(OH) 2 , -L-Y, or labeled derivative thereof; or R 1  and said α-carboxylate, when taken together, form a lactone having 4 to 7 ring atoms;   each R x  is independently (C 1 -C 20 )alkylenyl;   R y  is (C 1 -C 6 )alkyl, (C 5 -C 50 )aryl(C 1 -C 6 )alkyl, (C 5 -C 50 )aryloxy(C 1 -C 6 )alkyl, hydroxyl, (C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl, N(R 3 ) 2 , (C 5 -C 50 )aryl, (C 3 -C 50 )heteroaryl having at least one heteroatom selected from N, O, and S; heterocyclyl, (C 5 -C 50 )aryl(C 1 -C 6 )alkyl, or (C 3 -C 50 )heteroaryl(C 1 -C 6 )alkyl;   R z  is (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —R x —O—(C 1 -C 6 )alkyl, (C 5 -C 50 )aryl, (C 3 -C 50 )heteroaryl having at least one heteroatom selected from N, O, and S; (C 5 -C 50 )aryl(C 1 -C 6 )alkyl, or (C 3 -C 50 )heteroaryl(C 1 -C 6 )alkyl;   R 3  is, independently, H, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyl-N(R 4 ) 2 ;   R 4  is, independently, H or (C 1 -C 6 )alkyl;   R 5  is —C(═O)—(C 1 -C 6 )alkyl, —C(═O)—(C 5 -C 50 )aryl, —SO 2 —(C 5 -C 50 )aryl, —C(═O)NR 3 R 4 , —C(═O)—NR 4 (C 5 -C 50 )aryl, or —C(═O)-heterocycle;   or R 3  and R 5  together form a (C 2 -C 10 )heterocycloalkyl;   L is an aliphatic or aromatic linkage; Y is a residue of an imageable moiety, peptide, peptidomimetic, or carbohydrate.   
     
     
         4 . The compound according to  claim 3 , wherein said L aliphatic linkage is divalent alkylenyl group, and said aromatic linkage is a divalent aryl group. 
     
     
         5 . The compound according to  claim 1 , wherein:
 R 1  is (C 1 -C 20 )alkyl, hydroxy(C 1 -C 20 )alkyl, hydroxy(C 2 -C 20 )alkenyl, (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, halo, (C 5 -C 50 )aryl, (C 3 -C 50 )heteroaryl having at least one heteroatom selected from N, O, and S; (C 5 -C 50 )aryl(C 1 -C 20 )alkyl, (C 3 -C 50 )heteroaryl(C 1 -C 20 )alkyl, (C 5 -C 50 )aryloxy(C 1 -C 20 )alkyl, (C 3 -C 50 )heteroaryloxy(C 1 -C 20 )alkyl, (C 5 -C 50 )arylamino(C 1 -C 20 )alkyl, heteroarylamino(C 1 -C 20 )alkyl, amino(C 1 -C 20 )alkyl, —R x —C(═O)—R y , —R x —C(═O)—O—R y , —R x —O—R z , —R x —O—R x —NR 3 R 5 , -L-Y, or labeled derivative thereof; or R 1  and said α-carboxylate, when taken together, form a lactone having 4 to 7 ring atoms;   each R x  is independently (C 1 -C 6 )alkylenyl;   R y  is (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, N(R 3 ) 2 , (C 5 -C 50 )aryl, (C 3 -C 50 )heteroaryl having at least one heteroatom selected from N, O, and S; (C 5 -C 50 )aryl(C 1 -C 6 )alkyl, or (C 3 -C 50 )heteroaryl(C 1 -C 6 )alkyl;   R z  is (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 5 -C 50 )aryl, (C 3 -C 50 )heteroaryl having at least one heteroatom selected from N, O, and S; (C 5 -C 50 )aryl(C 1 -C 6 )alkyl, or (C 3 -C 50 )heteroaryl(C 1 -C 6 )alkyl;   R 3  is, independently, H or (C 1 -C 6 )alkyl;   L is an aliphatic or aromatic linkage;   Y is a residue of an imageable moiety, peptide, peptidomimetic, or carbohydrate.   
     
     
         6 . The compound according to  claim 1 , wherein:
 X 2  is —S— or —O—.   
     
     
         7 . The compound according to  claim 1 , wherein:
 X 2  is —S—.   
     
     
         8 . The compound according to  claim 1 , wherein:
 X 3  is —(NR 2 )—.   
     
     
         9 . The compound according to  claim 1 , wherein:
 R 2  is H.   
     
     
         10 . The compound according to  claim 1 ,
 wherein Y is a residue of an imageable moiety comprises a functional moiety selected from the group consisting of a gamma ray emitting radioisotope, a positron emitting radioisotope, a magnetic resonance imaging contrast agent, an X-ray contrast agent, or an ultrasound contrast agent.   
     
     
         11 . The compound according to  claim 4 ,
 wherein R 1  is a fluorescently-labeled derivative thereof.   
     
     
         12 . The compound according to  claim 4 ,
 R 1  is (C 1 -C 20 )alkyl, hydroxy(C 1 -C 20 )alkyl, (C 2 -C 20 )alkenyl, (C 5 -C 50 )aryl, (C 5 -C 50 )aryl(C 1 -C 20 )alkyl, (C 3 -C 50 )heteroaryl(C 1 -C 20 )alkyl, (C 5 -C 50 )aryloxy(C 1 -C 20 )alkyl, amino(C 1 -C 20 )alkyl, —R x —C(═O)—R y , —R x —O—R z , —R x —NR 3 R 5 , —R x —O—C(═O)—R y , (C 1 -C 6 )alkyl-B—(OH) 2 , -L-Y, or labeled derivative thereof or R 1  and said α-carboxylate, when taken together, form a lactone having 4 to 7 ring atoms.   
     
     
         13 . The compound according to  claim 4 ,
 R x  is (C 1 -C 6 )alkylenyl.   
     
     
         14 . The compound according to  claim 4 ,
 R y  is hydroxyl, (C 1 -C 6 )alkoxy, N(R 3 ) 2 , or heterocyclyl.   
     
     
         15 . The compound according to  claim 4 ,
 R z  is —R x —O—(C 1 -C 6 )alkyl.   
     
     
         16 . The compound according to  claim 4 ,
 R 4  is, independently, H or (C 1 -C 4 )alkyl.   
     
     
         17 . The compound according to  claim 4 ,
 R 5  is —C(═O)—(C 1 -C 6 )alkyl, —C(═O)—(C 5 -C 10 )aryl, —SO 2 —(C 5 -C 10 )aryl, —C(═O)NR 3 R 4 , —C(═O)—NR 4 (C 5 -C 10 )aryl, or —C(═O)-heterocycle.   
     
     
         18 . The compound according to  claim 4 ,
 wherein R 1  is selected from the group consisting of the sidechains illustrated in  FIGS. 19-24  in the attached drawings.   
     
     
         19 . The compound according to  claim 1 , wherein said compound is selected form the group consisting of:
 2-Amino-2-benzyl-6-boronohexanoic acid;   2-Allyl-2-amino-6-boronohexanoic acid;   2-Amino-2-(4-boronobutyl)succinic acid;   2-Amino-6-(borono-2-(3-phenoxypropyl)hexanoic acid;   2-Amino-6-borono-2-(4-phenylbutyl)hexanoic acid;   2-Amino-6-borono-2-(3-(4-chlorophenoxy)propyl)hexanoic acid;   2-Amino-6-borono-2-(3-(4-methoxyphenoxy)propyl)hexanoic acid;   2-Amino-6-borono-2-(3-(4-fluorophenoxy)propyl)hexanoic acid;   2-Amino-6-borono-2-(3-(4-nitrophenoxy)propyl)hexanoic acid;   2-Amino-2-(3-(benzo[d][1,3]dioxol-5-yloxy)propyl)-6-boronohexanoic acid;   2-Amino-6-borono-2-(3-(4-(trifluoromethyl)phenoxy)propyl)hexanoic acid;   2-Amino-6-borono-2-(3-(3-methoxyphenoxy)propyl)hexanoic acid;   2-Amino-6-borono-2-(3-(3-phenoxyphenoxy)propyl)hexanoic acid;   2-Amino-6-borono-2-(3-(3-isopropylphenoxy)propyl)hexanoic acid;   2-Amino-2-(3-(biphenyl-4-yloxy)propyl)-6-boronohexanoic acid;   2-Amino-2-(3-(biphenyl-3-yloxy)propyl)-6-boronohexanoic acid;   2-Amino-6-borono-2-(3-(3-(trifluoromethyl)phenoxy)propyl)hexanoic acid;   2-Amino-6-borono-2-(3-(4-(trifluoromethylthio)phenoxy)propyl)hexanoic acid;   2-Amino-6-borono-2-(3-(2,6-difluorophenoxy)propyl)hexanoic acid;   2-Amino-6-borono-2-(3-(o-tolyloxy)propyl)hexanoic acid;   2-Amino-6-borono-2-(3-(p-tolyloxy)propyl)hexanoic acid;   4-(4-Amino-8-borono-4 carboxyoctyloxy)benzoic acid;   2-Amino-2-(3-(4-aminophenoxypropyl)-6-boronohexanoic acid;   2-Amino-6-(borono-2-(pyridin-3-ylmethyl)hexanoic acid;   2-Amino-2-(benzyloxyethyl)-6-boronohexanoic acid;   2-Amino-6-borono-2-(2-methoxyethyl)hexanoic acid;   2-Amino-6-borono-2-(2-(p-tolyoxy)ethyl)hexanoic acid;   2-Amino-6-borono-2-(2-(3-chlorophenoxy)ethyl)hexanoic acid;   2-Amino-6-borono-2-(2-(2,3-dihydrobenzo[b][1,4]dioxin-5-yloxy)ethylhexanoic acid;   2-Amino-6-borono-2-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)hexanoic acid;   2-Amino-6-borono-2-(2-(3-methoxyphenoxy)ethyl)hexanoic acid;   2-Amino-6-borono-2-(2-(3-nitrophenoxy)ethyl)hexanoic acid;   2-Amino-6-borono-2-(2-(3-(morpholinosulfonyl)phenoxy)ethyl)hexanoic acid;   2-Amino-2-(2-(3-aminophenoxy)ethyl)-6-boronohexanoic acid;   2-Amino-6-borono-2-(3-hydroxypropyl)hexanoic acid;   2-Amino-6-borono-2-(4-boronobutyl)hexanoic acid;   2-Amino-2-(4-boronobutyl)hex-4-enoic acid;   2-Amino-6-borono-2-(2-(2-methoxyethoxy)ethyl)hexanoic acid;   2-Amino-6-borono-2-methylhexanoic acid;   2-Amino-6-borono-2-isobutylhexanoic acid;   2-Amino-6-borono-2-(hydroxymethyl)hexanoic acid;   (R)-2-Amino-6-borono-2-(hydroxymethyl)hexanoic acid;   (S)-2-Amino-6-borono-2-(hydroxymethyl)hexanoic acid;   2-Amino-2-(2-(benzyloxy)-2-oxoethyl)-6-boronohexanoic acid;   2-Amino-6-borono-2-(2-methoxy-2-oxoethyl)hexanoic acid;   2-Amino-6-borono-2-(cyanomethyl)hexanoic acid;   2-Amino-6-borono-2-(2-oxobutyl)hexanoic acid;   2-Amino-6-borono-2-(2-oxo-2-phenylethyl)hexanoic acid;   2-Amino-2-(2-(2-aminoethoxy)ethyl)-6-boronohexanoic acid;   2-Amino-6-borono-2-(3-(piperidin-4-yl)propyl)hexanoic acid;   2-Amino-6-borono-2-(3-(piperazine-1-yl)propylhexanoic acid;   2,6-Diamino-2-(4-boronobutyl)hexanoic acid;   2-Amino-6-borono-2-(2-(2-(4-cyanobenzamid)ethoxy)ethyl)hexanoic acid;   2-(2-(2-Acetamidoethoxy)ethyl)-2-amino-6-boronohexanoic acid;   2-Amino-6-borono-2-(2-(2-(3-(3-methoxyphenyl)ureido)ethoxy)ethyl)hexanoic acid;   2-(3-(1-Acetylpiperidin-4-yl)propyl)-2-amino-6-boronohexanoic acid;   2-Amino-6-borono-2-(3-(1-(3-methoxyphenylcarbamoyl)piperidin-4-yl)propyl)hexanoic acid;   2-(3-(4-Acetylpiperazin-1-yl)propyl)-2-amino-6-boronohexanoic acid;   2-Amino-6-borono-2-(3-(4-(4-cyanobenzoyl)piperazine-1-yl)propyl)hexanoic acid;   2-Amino-6-borono-2-(3-(4-(3-methoxyphenylcarbamoyl)piperazin-1-yl)propyl)hexanoic acid;   2-Amino-6-borono-2-(4-(4-methylphenylsulfonamido)butyl)hexanoic acid;   2-Amino-6-borono-2-(4-(3,5-difluorobenzamido)butyl)hexanoic acid;   2-Amino-6-(benzyloxycarbonylamino)-2-(4-boronobutyl)hexanoic acid;   6-Acetamido-2-amino-2-(4-boronobutyl)hexanoic acid;   2-amino-6-borono-2-(4-(3-(3-methoxyphenyl)ureido)butyl)hexanoic acid;   2-Amino-4-(2-hydroxyguanidino)-2-methylbutanoic acid; and   pharmaceutically acceptable salts thereof.   
     
     
         20 . The compound according to  claim 19 , wherein said pharmaceutically acceptable salts comprise at least one hydrochloric acid and trifluoroacetic acid addition salt of said compound. 
     
     
         21 . A composition, comprising:
 at least one compound of  claim 1  or a pharmaceutically acceptable salt thereof; and   a pharmaceutically-acceptable carrier.   
     
     
         22 . A method of inhibiting arginase in a mammal, comprising:
 administering to said mammal an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof.   
     
     
         23 . A method of treating an arginase-related disorder in a mammal, comprising:
 administering to said mammal an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof.   
     
     
         24 . The method according to  claim 23 ,
 wherein said arginase-related disorder is a disorder associated with an abnormally low level of nitric oxide synthase activity in a tissue of the human, a disorder associated with an abnormally high level of arginase activity in a tissue of the human, or combinations thereof.   
     
     
         25 . The method according to  claim 24 ,
 wherein said arginase-related disorder is heart disease, systemic hypertension, pulmonary hypertension, ischemia reperfusion injury, peripheral vascular disease, peripheral arterial disease, subarachnoid hemorrhage, erectile dysfunction, autoimmune encephalomyelitis, chronic renal failure, gastrointestinal motility disorders, gastric cancers, reduced hepatic blood flow, insufficient hepatic blood flow, cerebral vasospasm, or a combination thereof.   
     
     
         26 . A method of relaxing smooth muscle in a mammal, comprising:
 administering to said mammal an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof.   
     
     
         27 . The method according to  claim 26 ,
 wherein smooth muscle which is relaxed according to this method is at least one selected from the group consisting of a gastrointestinal smooth muscle, anal sphincter smooth muscle, esophageal sphincter muscle, corpus cavernosum, sphincter of Oddi, arterial smooth muscle, heart smooth muscle, pulmonary smooth muscle, kidney smooth muscle, uterine smooth muscle, vaginal smooth muscle, cervical smooth muscle, placental smooth muscle, and ocular smooth muscle.   
     
     
         28 . A method of diagnosing arginase overexpression in a patient, comprising the step of:
 administering to said patient a diagnostically-effective amount of a compound of  claim 3  or a pharmaceutically acceptable salt thereof   where R 1  is a labeled derivative thereof and   imaging said patient.   
     
     
         29 . The method according to  claim 28 ,
 wherein said arginase overexpression is associated with asthma, cancer, bacterial infections, or combinations thereof.   
     
     
         30 . A method of diagnosing arginase overexpression in a patient, comprising the step of:
 administering to said patient a diagnostically-effective amount of a compound of  claim 3  or a pharmaceutically acceptable salt thereof;   where Y is an imageable moiety; and   imaging said patient.   
     
     
         31 . The method according to  claim 30 ,
 wherein said arginase overexpression is associated with asthma, cancer, bacterial infections, or combinations thereof.   
     
     
         32 . A method for radioimaging a patient, comprising the steps of:
 administering to said patient an effective amount of a compound of  claim 3 , wherein Y is an imageable moiety; and   scanning said patient using a radioimaging device.   
     
     
         33 . The method of inhibiting arginase, comprising the step of:
 contacting said arginase with a compound of  claim 1  or a salt thereof.   
     
     
         34 . The method according to  claim 33 ,
 wherein said arginase is a yeast arginase, a bacterial arginase, a parasitic arginase, or a mammalian arginase.   
     
     
         35 . The method according to  claim 34 ,
 wherein said mammalian arginase is a human type I arginase or a human type II arginase.   
     
     
         36 . A diagnostic composition, comprising:
 a diagnostically-effective amount of the compound of  claim 3  or a pharmaceutically acceptable salt thereof, where R 1  is a labeled derivative thereof; and   a pharmaceutically acceptable carrier.   
     
     
         37 . A diagnostic composition, comprising:
 a diagnostically-effective amount of the compound of  claim 3  or a pharmaceutically acceptable salt thereof, where Y is an imageable moiety; and   a pharmaceutically acceptable carrier.   
     
     
         38 . A method of treating a disease or condition associated with upregulation of arginase in a mammal, comprising the step of:
 administering to said mammal an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof;   wherein said disease or condition is a gastrointestinal disease, a pulmonary inflammatory disease, a sexual arousal disorder, a cardiovascular disorder, a hemolytic disorder, an autoimmune disease, wound healing, a disease caused by parasitic protozoa, a disease caused by bacteria, a cancer, pre-term labor, psoriasis, or a combination thereof.   
     
     
         39 . The method according to  claim 38 ,
 wherein said gastrointestinal disease is a gastrointestinal motility disorder, inflammatory bowel disease, Crohn's disease, ulcerative colitis, gastric ulcer, adenotonsilar disease, or a combination thereof.   
     
     
         40 . The method according to  claim 38 ,
 wherein said pulmonary inflammatory disease is asthma, chemically-induced lung fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary disease (COPD) or a combination thereof.   
     
     
         41 . The method according to  claim 38 ,
 wherein said sexual arousal disorder is male erectile dysfunction, Peyronie's Disease, or a female sexual arousal disorder.   
     
     
         42 . The method according to  claim 38 ,
 wherein said cardiovascular disorder is endothelial vascular dysfunction in atherosclerosis, hypertension, ischemia reperfusion injury, peripheral vascular disease, peripheral arterial disease, subarachnoid hemorrhage, hypercholesterolemia, diabetes, or a combination thereof, diabetic cardiovascular disease, pulmonary arterial hypertension, Reynaud's disease or a combination thereof.   
     
     
         43 . The method according to  claim 38 ,
 wherein said hemolytic disorder is paroxysmal nocturnal hemoglobinuria (PNH), sickle-cell disease, thalassemias, hereditary spherocytosis and stomatocytosis, microangiopathic hemolytic anemias, pyruvate kinase deficiency, ABO mismatch transfusion reaction, paroxysmal cold hemoglobinuria, severe idiopathic autoimmune hemolytic anemia, infection-induced anemia, malaria, cardiopulmonary bypass, mechanical heart valve-induced anemia, chemical induced anemia, or a combination thereof.   
     
     
         44 . The method according to  claim 38 ,
 wherein said autoimmune disease is encephalomyelitis, multiple sclerosis, anti-phospholipid syndrome 1, autoimmune hemolytic anaemia, chronic inflammatory demyelinating polyradiculoneuropathy, dermatitis herpetiformis, dermatomyositis, myasthenia gravis, pemphigus, rheumatoid arthritis, stiff-person syndrome, type 1 diabetes, ankylosing spondylitis, or a combination thereof.   
     
     
         45 . The method according to  claim 38 ,
 wherein said condition is wound healing.   
     
     
         46 . The method according to  claim 38 ,
 wherein said disease caused by parasitic protozoa is African sleeping sickness, Chagas' disease, leishmaniasis, malaria, or a combination thereof.   
     
     
         47 . The method according to  claim 38 ,
 wherein said cancer is renal cell carcinoma, prostate cancer, colorectal cancer, breast cancer, skin cancer, lung cancer, ovarian cancer, gastric cancer, or a combination thereof.   
     
     
         48 . The method according to  claim 47 ,
 wherein said skin cancer is a squamous cell cancer, basal cell cancer, or a combination thereof.   
     
     
         49 . The method according to  claim 38 ,
 wherein said condition is pre-term labor.   
     
     
         50 . The method according to  claim 38 ,
 wherein said condition is psoriasis.   
     
     
         51 . A method of providing relief from immune suppression in a mammal, comprising the step of:
 administering to said mammal an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof;   wherein said mammal is suffering from a disease or condition selected from the group consisting of a chronic infectious disease, a bacterial infection, a parasitic infection, trauma, leprosy, tuberculosis, liver transplantation, a cancer, and combinations thereof.   
     
     
         52 . A method of inhibiting the production of ornithine in a mammal suffering from at least one tumor, comprising the step of:
 administering to said mammal an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof.   
     
     
         53 . A composition, comprising:
 a compound of  claim 1  or a pharmaceutically acceptable salt thereof;   a phosphodiesterase-1 (PDE1) inhibitor, a phosphodiesterase-2 (PDE2) inhibitor, a phosphodiesterase-5 (PDE5) inhibitor, or a non-specific PDE inhibitor that inhibits PDE1, PDE2, PDE5, or a combination thereof; and   optional pharmaceutically-acceptable excipient.   
     
     
         54 . A process for preparing a substituted boronic acid of formula I: 
       
         
           
           
               
               
           
         
         or stereoisomer, lactone prodrug, or pharmaceutically-acceptable salt thereof; 
         said process comprising: 
         reacting in a solution phase, in the presence of a iridium catalyst, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane with a compound of formula II: 
       
       
         
           
           
               
               
           
         
         to form a boronate ester product; and 
         deprotecting said boronate ester product to form said compound of formula I; 
         wherein:
 R is methyl, ethyl, or t-butyl; 
 
         Z is 
       
       
         
           
           
               
               
           
         
         X 1  is —(CH 2 )—; 
         X 2  is —(CH 2 )—; 
         X 3  is —(CH 2 )—; 
         X 4  is —(CH 2 )—; 
         R 1  is a monovalent moiety other than H; or R 1  and said α-carboxylate, when taken together, form a lactone. 
       
     
     
         55 . The process according to  claim 54 ,
 wherein said iridium catalyst is [Ir(cod)Cl] 2 .   
     
     
         56 . The process according to  claim 54 ,
 wherein said deprotecting step is carried out in the presence of a strong aqueous acid.   
     
     
         57 . A method of inhibiting arginase in patient in need thereof, comprising:
 administering to said patient an effective amount of a borono-substituted α,α-disubstituted α-amino carboxylic acid or a pharmaceutically acceptable salt thereof.   
     
     
         58 . A method of treating or preventing a arginase-mediated malady in patient in need thereof, comprising:
 administering to said patient an effective amount of a borono-substituted α,α-disubstituted α-amino carboxylic acid or a pharmaceutically acceptable salt thereof, such that said malady is treated or prevented.   
     
     
         59 . A method of inhibiting arginase in patient in need thereof, comprising:
 administering to said patient an effective amount of a guanidino-substituted α,α-disubstituted α-amino carboxylic acid or a pharmaceutically acceptable salt thereof.   
     
     
         60 . A method of treating or preventing a arginase-mediated malady in patient in need thereof, comprising:
 administering to said patient an effective amount of a guanidino-substituted α,α-disubstituted α-amino carboxylic acid or a pharmaceutically acceptable salt thereof, such that said malady is treated or prevented.   
     
     
         61 . The compound according to  claim 1 , wherein X 1 , X 2 , and X 3  together are —(CH 2 ) n —, n being an integer from 1 to 6, and wherein Z is —B(OH) 2 . 
     
     
         62 . The compound according to  claim 61 , wherein said compound has L-stereochemistry. 
     
     
         63 . The compound according to  claim 61 , wherein n is 4. 
     
     
         64 . The compound according to  claim 1 , wherein X 1 , X 2 , and X 3  together are —(CH 2 ) n (NH)—, n being an integer from 1 to 6, and wherein Z is 
       
         
           
           
               
               
           
         
       
     
     
         65 . The compound according to  claim 64 , wherein said compound has L-stereochemistry. 
     
     
         66 . The compound according to  claim 64 , wherein n is 2. 
     
     
         67 . The compound according to  claim 3 , wherein said R 1  group comprises a amino nitrogen atom that is substituted with one or more R a  groups.