Pharmaceutical Properties of Related Calanolide Compounds with Activity against Human Immunodeficiency Virus

Abstract

The present studies were undertaken to compare the relative pharmacokinetic parameters and bioavailability of two chemically related natural products which are nonnucleoside inhibitors of reverse transcriptase. Both (+)-calanolide A (Cal A; NSC 675451) and (+)-dihydrocalanolide A (DHCal A; NSC 678323) are currently under development for the treatment of HIV infections. HPLC-based analytical assays were developed for both compounds using modifications of a previously published procedure. The assays were used to compare the intravenous pharmacokinetics of the dihydro analogue relative to the parent compound, Cal A, and to determine the relative oral bioavailability of each drug in CD2F1 mice. Although the pharmacokinetic parameters of each drug were similar (Cal A, 25 mg/kg: AUC: 9.4 [microg/mL]. hr, t1/2beta: 0.25 h,, t1/2gamma: 1.8 h, clearance: 2.7 L/h/kg versus DHCal A, 25 mg/kg: AUC: 6.9 [microg/mL].hr, t1/2beta: 0.22 h,, t1/2gamma: 2.3 h, clearance: 3.6 L/h/kg), the oral bioavailability of DHCal A (F = 46. 8%) was markedly better than that obtained for Cal A (F = 13.2%). The relative ability of Cal A and DHCal A to change to their inactive epimer forms, (+)-calanolide B and (+)-dihydrocalanolide B, respectively, was also determined. While conversion of active to inactive forms of the drugs was noted to occur in vitro especially under acidic conditions, no epimer forms of either compound were noted in plasma of mice after administration of either CalA or DHCal A. Considered together with preliminary toxicology findings, the pharmacokinetic data obtained in the present series of experiments suggest that selection of the dihydro derivative of (+)-calanolide A may be a reasonable choice for further preclinical development and possible Phase I clinical evaluation.

Review on Natural Coumarin Lead Compounds for Their Pharmacological Activity

“…(+)-Calanolide A is a nonnucleoside RT inhibitor with potent activity against HIV-1. (−)-Calanolide B and (−)-dihydrocalanolide B ( 26 ) possess antiviral properties similar to those of (+)-calanolide A [35, 62]. Both (+)-calanolide A and (+)-dihydrocalanolide A ( 27 ) are stable at neutral pH and currently under development for the treatment of HIV infections.…”

“…Both (+)-calanolide A and (+)-dihydrocalanolide A ( 27 ) are stable at neutral pH and currently under development for the treatment of HIV infections. However, at a pH < 2.0 for 1 h, 73% of the (+)-calanolide A was converted to (+)-calanolide B while 83% of (+)-dihydrocalanolide A was converted to (+)-dihydrocalanolide B [35, 62]. Previously inophyllum A ( 17 ) and (−)-calanolide B ( 25 ) were isolated from the oil of seeds of Calophyllum inophyllum Linn and Calophyllum cerasiferum Vesque, respectively.…”

Plant-Derived Leading Compounds for Chemotherapy of Human Immunodefiency Virus (HIV) Infection – An Update (1998 – 2007)

“…Cordatolides A (26) and B (27) were about 50 times less active against HIV-1 reverse transcriptase than (+)-calanolide A, indicating that the nature of C-4 substitution is important [54]. (+)-Calanolide A has been extensively studied because of its unique sensitivity/resistance profile [55]; [56], its synergistic effect in combination with other anti-HIV drugs [57] and its pharmacokinetic profile [58], [59], [60], [61], [62]. The interaction of NNRTIs at the hydrophobic non-nucleoside binding site of HIV-1 reverse transcriptase is highly specific.…”

Recent progress in the development of coumarin derivatives as potent anti‐HIV agents

“…114 was more orally bioavailable than 101 without losing anti-HIV activity (F ¼ 46.8 and 13.2%, respectively). 50 Compound 101 is synthesized from phloroglucinol in five steps and is being investigated for clinical research. [51][52][53][54] A phase IA studies showed that 101 was generally well tolerated in doses up to 600 mg.…”