Hypolipidaemic activity in rodents of boron analogs of phosphonoacetates and cyanoborane adducts of dialkyl aminomethylphosphonates.
Boron analogues of phosphonoacetates proved to be potent hypolipidaemic agents in rodents, lowering both serum cholesterol and triglyceride levels. (C2H5O)3PBH2COOCH3 proved to be the most effective agent in mice, lowering serum cholesterol 46% and serum triglycerides 54% after 16 days. (C2H5O)3PBH2COOH and Na+H+(C2H5O)2(-O)PBH2COO- caused greater than a 40% reduction in lipids. The cyanoborane adducts of aminomethylphosphonates were generally less effective; (C6H5O)2P(O)CH2NH2BH2CN was the most effective, lowering serum cholesterol 32% and serum triglycerides 43% after 16 days. The phosphonoacetates appeared to lower lipid concentrations by several mechanisms. First, they lowered the de novo synthesis of cholesterol and triglycerides in the liver. Second, they accelerated the excretion of lipids into the bile and faeces. Thirdly, they modulated LDL and HDL-cholesterol contents in a manner which suggests they reduced the deposition of lipids in peripheral tissues, and accelerated the movement of cholesterol from tissues (e.g. plaques) to the liver for excretion into the bile.
Hall
I H
IH
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27599.
Wong
O T
OT
Sood
A
A
Sood
C K
CK
Spielvogel
B F
BF
Shrewsbury
R P
RP
Morse
K W
KW
D000818:Animals; D001011:Aorta / Q000737:chemistry; D001646:Bile / Q000737:chemistry; D001895:Boron / Q000494:pharmacology; D001896:Boron Compounds / Q000494:pharmacology*; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood*; D005243:Feces / Q000737:chemistry; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007421:Intestine, Small / Q000737:chemistry; D008055:Lipids / Q000032:analysis* / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010746:Phosphonoacetic Acid / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014280:Triglycerides / Q000097:blood*
D001896:Boron Compounds; D000960:Hypolipidemic Agents; D008055:Lipids; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D014280:Triglycerides; C076461:(cyano-C)(diphenyl(aminomethyl)phosphonate-N)dihydroboron; C076462:(methylcarboxy-C)(triethylphosphonate-P)dihydroboron; D002784:Cholesterol; D010746:Phosphonoacetic Acid; D001895:Boron