Carbamoylphosphonate matrix metalloproteinase inhibitors 6: cis-2-aminocyclohexylcarbamoylphosphonic acid, a novel orally active antimetastatic matrix metalloproteinase-2 selective inhibitor--synthesis and pharmacodynamic and pharmacokinetic analysis.
cis-2-Aminocyclohexylcarbamoylphosphonic acid ( cis-ACCP) was evaluated in vitro and in two in vivo cancer metastasis models. It reduced metastasis formation in mice by approximately 90% when administered by a repetitive once daily dosing regimen of 50 mg/kg via oral or intraperitoneal routes and was nontoxic up to 500 mg/kg, following intraperitoneal administration daily for two weeks. Pharmacokinetic investigation of cis-ACCP in rats revealed distribution restricted into the extracellular fluid, which is the site of action for the antimetastatic activity and rapid elimination ( t 1/2 approximately 19 min) from blood. Sustained and prolonged absorption ( t 1/2 approximately 126 min) occurred via paracellular mechanism along the small and large intestine with overall bioavailability of 0.3%. The in vivo concentrations of cis-ACCP in the blood in rats was above the minimal concentration for antimetastatic/MMP-inhibitory activity, thus explaining the prolonged action following once daily administration. Finally, 84% of the intravenously administered cis-ACCP to rats was excreted intact in the urine.
Hoffman
Amnon
A
Department of Pharmaceutics, The Hebrew University of Jerusalem, Jerusalem, Israel. amnonh@ekmd.huji.ac.il
Qadri
Bashir
B
Frant
Julia
J
Katz
Yiffat
Y
Bhusare
Sudhakar R
SR
Breuer
Eli
E
Hadar
Rivka
R
Reich
Reuven
R
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D045744:Cell Line, Tumor; D003038:Cobamides; D003510:Cyclohexanes; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D051381:Rats; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D023382:Toxicity Tests, Acute
D000970:Antineoplastic Agents; D003038:Cobamides; D003510:Cyclohexanes; D061965:Matrix Metalloproteinase Inhibitors; D063065:Organophosphonates; C465815:adenosylcobinamide 2-chlorophenyl phosphate