SSAO inhibitors

Aromatic side chain-fluorinated MAO and SSAO inhibitors 671... 

AROMATIC SIDE CHAIN-FLUORINATED MAO AND SSAO INHIBITORS... 

A. O Rourke, M.D. Linnik, Design, synthesis, and biological evaluation of semicarba-zide-sensitive amine oxidase (SSAO) inhibitors with anti-inflammatory activity, J. Med. Chem. 49 (2006) 2166-2173. 

S)-[ F]fluoroethylcarazolol 8, 111 subtypes of, 100 Adriamycine (doxorubicine), 589 Agrochemical agents, 215 AIF. See Aluminium monofluoride Aliphatic nucleophilic substitution, 28 Alkenes, as amide bond substitutes, 702-703 Alkenes fluorination, 18 Allyl hydrazines as SSAO inhibitors, 674 Aluminium monofluoride, 534 Alumino-fluoride complexes, 364 Alzheimer s disease (AD)... 

For those interested in the discovery of drug candidates to attenuate SSAO/ VAP-1 activity there are two properties that need to be considered. First, as mentioned above, SSAO/VAP-1 exists as a membrane bound protein and a truncated version is found in the plasma [10,11]. Second, there is tremendous species variation which is revealed in a very large range of the second order rate constant V/K, using benzylamine as substrate, [22,23], and that inhibitor potencies vary widely according to the species [24,25]. Furthermore, within a single species specific activity varies from tissue to tissue [26]. 

A group from La Jolla Pharmaceuticals has released data on their novel hydrazines in recent scientific [20,59,60] and patent literature [61,62], A series of arylallyl hydrazines (e.g., 8 and 9) were shown to be potent, irreversible inhibitors of rat and human SSAO/VAP-1 [59]. LJP-1207 (8, IC50 = 2nM, human) was evaluated in a series of in vivo inflammation models. Significant efficacy was observed in a mouse ulcerative colitis, mouse LPS-induced septic shock, and the rat carrageenan foot models [20], in a mouse model that resembles human multiple sclerosis [63], and in a transient forebrain ischemia model in estrogen-treated ovariectomized female rats [60]. 

Two laboratories have independently disclosed an interesting series of mechanism-based inhibitors. The dihydropyrrole 31, which appeared in a patent application [61], was reported to inhibit rat lung SSAO/VAP-1 with an IC50 = 500 nM. Recently, the Sayre team extended earlier work [74] and showed that these inhibitors, exemplified by 32, covalently bound to the enzyme with the cofactor in the reduced form [75]. Presumably, aromatization of the dihydropyrrole moiety accounts for the observed potencies. 

Other inhibitors include alginic acid hydroxamates [80], the natural products myricetin galloylglycosides [81], polyaminoglycosides [82] and a number of antidepressant drugs [83] which demonstrate various degree of SSAO/VAP-1 inhibitory property in rats, humans and cows. 

Haloallyl amines also have been studied as inhibitors of SSAO. The 2-aryl-3-haloallylamines proved to be potent irreversible inhibitors of rat aorta SSAO. Hydrophobic substituents on the aryl ring enhanced activity, while phenolic groups decreased activity [78]. The MAO B selective ( )-2-(3, 4 -dimethoxyphe-nyl)-3-fluoroallylamine (22d) inhibited rat SSAO in vascular and brown adipose tissues and was selective relative to inhibition of MAO A [79]. MDL 72974A (25) is a potent irreversible inhibitor of both MAO B and SSAO with a 190-fold lower affinity for MAO A [80]. 

Carbonyl reagents, such as semicarbazide and phenelzine (27), are inactivators of SSAO. In a strategy that includes two inactivating structural motifs (allylamine and hydrazine), a series of allyl hydrazines including the series 28a-c as well as the fluoroallyl analogue 29 were prepared. Compounds 28a-c were potent irreversible inhibitors of SSAO, and compounds 28a,c had particularly good selectivity with respect to MAO inhibition. The presence of the vinyl fluoride in 29 had little effect on potency but did result in a loss in selectivity [82]. 

TraA7s-2-phenylcyclopropylamine (8a) and its c/ s-isomer (8b) are competitive inhibitors of microbial copper-containing SSAO [37,130], Introduction of fluorine at position 2 of 8a and 8b had dramatic effects on the inhibition of microbial tyra-mine oxidase from Arthrobacter sp. by these compounds [130], Compound 60a with a cis arrangement of the fluorine substituent and the amino group was 10 times more potent an inhibitor than compound 8a. In contrast, the corresponding diastereomer 61a with a trans arrangement of the two substituents was five times less active than 8a (Table 3). 

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