Synthesis of novel N-phosphonoalkyl dipeptide inhibitors of human collagenase.
The synthesis of a series of N-phosphonalkyl dipeptides 6 is described. Syntheses were devised that allowed the preparation of single diastereoisomers and the assignment of stereochemistry. The compounds were evaluated in vitro for their ability to inhibit the degradation of radiolabeled collagen by purified human lung fibroblast collagenase. Several of the compounds were potent collagenase inhibitors and were at least 10-fold more potent than their corresponding N-carboxyalkyl analogues. Activity was lost when the phosphonic acid group P(O)(OH)2 was replaced by the phosphinic acid groups P(O)(H)(OH) and P(O)(Me)(OH). At the P1 position, (R)- or (S)-alkyl groups, especially ethyl and methyl (e.g., 12a,b, 52a,b, and 53a,b), or an (R)-phenethyl moiety (55a) conferred high potency (IC50 values in the range 0.23-0.47 microM). (S)-Stereochemistry was preferred for the P1' isobutyl side chain. Structure-activity relationships were also investigated at the P2' site, and interestingly, compounds with basic side chains, such as the guanidine 57a, were equipotent with more lipophilic compounds, such as 52a. As with other series of collagenase inhibitors, potency was enhanced by introducing bicyclic aromatic P2' substituents. The most potent phosphonic acid of the series was the bicyclic aromatic P2' tryptophan analogue 59a (IC50 0.05 microM).
Bird
J
J
SmithKline Beecham Pharmaceuticals, Discovery Research, Harlow, Essex, U.K.
De Mello
R C
RC
Harper
G P
GP
Hunter
D J
DJ
Karran
E H
EH
Markwell
R E
RE
Miles-Williams
A J
AJ
Rahman
S S
SS
Ward
R W
RW
D000818:Animals; D001665:Binding Sites; D002264:Carboxylic Acids / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D017364:Collagenases / Q000737:chemistry / Q000378:metabolism; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D008968:Molecular Conformation; D015394:Molecular Structure; D063065:Organophosphonates / Q000737:chemistry / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry; D010721:Phosphinic Acids / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002264:Carboxylic Acids; D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; D063065:Organophosphonates; D010721:Phosphinic Acids; D003094:Collagen; D007703:Peptidyl-Dipeptidase A; D017364:Collagenases