ABSTRACT
The SAR of a series of 2-(7-chromanyl)benzoic acids has been investigated with the aim of identifying potent and selective LTB4 receptor antagonists that maintain potency in complex biological fluids. We found optimal activity in derivatives with electron-withdrawing groups in the benzoic acid ring and with an unsubstituted C-3 benzyl group on the chromanol nucleus. While compounds containing a 3-(4-phenyl)benzyl chromanol substituent were potent LTB4 receptor antagonists, the increased lipophilicity imparted by the additional phenyl substituent led to decreased potency in the presence of plasma proteins. From among the potent compounds identified, CP-195543, the 5'-trifluoromethyl 3-benzyl chromanol, was selected for development.
Subject(s)
Benzoates/pharmacology , Receptors, Leukotriene B4/antagonists & inhibitors , Animals , Benzoates/chemistry , Benzoates/metabolism , Blood Proteins/metabolism , Guinea Pigs , Humans , Macrophage-1 Antigen/metabolism , Neutrophils/drug effects , Neutrophils/metabolism , Receptors, Leukotriene B4/metabolism , Structure-Activity RelationshipABSTRACT
Small molecule FKBP inhibitors were prepared with inhibitory activity ranging from micromolar to nanomolar. The design of these inhibitors derives from a structural analysis of the substrates for FKBP and cyclophilin. As a consequence of this analysis two key observations were made, namely: (1) amino ketone moieties are suitable as FKBP recognition elements at the P1-P1' site and (2) the P3'-P4' site will accept a trans-olefin as a suitable mimetic of a peptide moiety. The preparation of these non-peptide inhibitors is readily accomplished by a protocol which includes the synthesis of chiral propargylic amines and their subsequent conversion into vinyl zirconium reagents.
Subject(s)
Amino Acids/chemical synthesis , Carrier Proteins/antagonists & inhibitors , Ketones/chemical synthesis , Amino Acid Isomerases/chemical synthesis , Amino Acid Isomerases/pharmacology , Amino Acids/pharmacology , Carrier Proteins/chemical synthesis , Carrier Proteins/pharmacology , Ketones/pharmacology , Peptidylprolyl Isomerase , Stereoisomerism , Structure-Activity Relationship , Tacrolimus Binding ProteinsABSTRACT
A series of erythromycin A-derived semisynthetic antibiotics, featuring incorporation of a basic nitrogen atom into a ring expanded (15-membered) macrocyclic lactone, have been prepared and biologically evaluated. Semisynthetic modifications focused upon (1) varied substitution at the macrocyclic ring nitrogen and (2) epimerization or amine substitution at the C-4'' hydroxyl site within the cladinose sugar. In general, the new azalides exhibit improved Gram-negative potency, expanding the spectrum of erythromycin A to fully include Haemophilus influenzae and Neisseria gonorrhoeae. When compared to erythromycin A, the azalides exhibit substantially increased half-life and area-under-the-curve values in all species studied. The overall in vitro/in vivo performance of N-methyl, C-4'' epimers 3a and 9; and C-4'' amine 11 identify these compounds as the most interesting erythromycin A-superior agents. Compound 3a has been advanced to clinical study.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Aza Compounds/chemical synthesis , Erythromycin/analogs & derivatives , Animals , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Aza Compounds/pharmacokinetics , Aza Compounds/pharmacology , Chemical Phenomena , Chemistry , Dogs , Erythromycin/chemical synthesis , Erythromycin/pharmacokinetics , Haplorhini , Microbial Sensitivity Tests , Molecular Conformation , RatsABSTRACT
Ring contraction of the neutral oleandrose sugar in the 14-membered-ring macrolide antibiotic oleandomycin (2) has been accomplished using [(methoxycarbonyl)sulfamoyl]triethylammonium hydroxide inner salt (1). The product of this interesting rearrangement, after methanolic hydrolysis of the 2'-acetate, is the 11-acetyl-3-O-(3"-methoxy-4"-vinylfuranosyl)oleandomycin (12). The in vitro activity of furanoside 12 is only moderately less than that of 11-acetyloleandomycin (13).
