Preclinical safety evaluation of low molecular weight heparin–deoxycholate conjugates as an oral anticoagulant

Abstract

The preclinical safety of a newly developed oral anticoagulant, the low molecular weight heparin-deoxycholate conjugate (OH09208), was evaluated by a comprehensive evaluating program in compliance with standard guidelines. The single dose oral toxicity study in rats receiving 2000 and 5000 mg kg(-1) of OH09208 did not reveal any mortality, unusual body weight changes or necropsy findings. The results of the 4-week oral toxicity study with a 4-week recovery program in rats receiving OH09208 in doses of 100, 300 and 1000 mg kg(-1) day(-1) did not reveal any mortality, or indicate any unusual clinical signs, or show any toxicokinetic relationships to the administration of OH09208. Although the increase in liver enzymes in one male dog treated with 300 mg kg(-1) day(-1) and one female dog treated with 1000 mg kg(-1) day(-1) could not be excluded from the effect of the test substance, no other toxicologically significant changes were observed in the 4-week oral toxicity study with a 4-week recovery in beagle dogs. Thus, while the no-observed-adverse-effect level value from the 4-week study in both male and female rats was 1000 mg kg(-1) day(-1), those from the 4-week study in male and female beagle dogs were 300 and 1000 mg kg(-1) day(-1), respectively. Furthermore, OH09208 did not induce anaphylactic reactions in guinea pigs, micronucleated bone marrow cells in male ICR mice, chromosomal aberration in Chinese hamster lung cell lines, bacterial reverse mutation, and any abnormalities in hERG current assay, mouse central nervous system and dog cardiovascular studies. Overall, there were no unexpected toxicities in this preclinical study that might have precluded the safe administration of OH09208 to humans.

A Comprehensive Review on Steroidal Bioconjugates as Promising Leads in Drug Discovery

“…Steroids have been used in the pharmaceutical market from early times. They are one of the leading molecules in the global market playing a variety of biological roles like antineoplastic agents, − antimicrobial agents, − adjuvants in anticoagulant agents, , anti-inflammatory agents, , antiviral agents, insecticides and pesticides, − antioxidants, , and cell imaging agents. , Due to their varied bioactivities, steroids serve as a convenient moiety to attach a large number of nonsteroidal pharmacophores for improving physicochemical and biological profiles such as increased lipid solubility, target specificity, or receptor selectivity . The rigid framework of the steroid nucleus helps them to penetrate the cell membrane and bind to the specific hormonal receptor; therefore, they have become preferred motifs for the design of bioconjugates with diverse biological profiles. , …”

“…Many more studies proved the improved oral bioavailability and the intestinal absorption of the heparin–DOCA conjugates. − Later on, the DOCA–heparin conjugate 89 was subjected to preclinical safety evaluation using several in vivo toxicity tests, and no unexpected toxicity, mutagenicity, or genotoxicity was found . Conjugation of DOCA to heparin via an ethylenediamine linker between free −COOH groups further enhanced the healing process from microvascular surgery.…”

“… 174 − 178 Later on, the DOCA–heparin conjugate 89 was subjected to preclinical safety evaluation using several in vivo toxicity tests, and no unexpected toxicity, mutagenicity, or genotoxicity was found. 39 Conjugation of DOCA to heparin via an ethylenediamine linker between free −COOH groups further enhanced the healing process from microvascular surgery. The anticoagulant activity of the conjugate measured by FXa chromogenic assay was found to be 86 IU/mg.…”

Quasi-Podands with 1,2,3-Triazole Rings from Bile Acid Derivatives: Synthesis, and Spectroscopic and Theoretical Studies

“…On the other hand, quasi-podands have a rigid benzene “platform” that allows them to obtain a conformer with appropriate geometry. Also, it can be crucial during interaction with the surface of biopolymers or acting as an “anchor” in biological systems. , Such systems have found application as carriers of biological molecules, hydrogelators, organogelators, or artificial receptors. − …”