The full-scale commercial appearance of
antibiotics in the 1950's caused a shift of the nature of our lethal diseases from infectious/acute to non-infectious/chronic. In this situation,
biological response modifiers (BRM's), which are not based on selective toxicity, are expected to be useful. There exist several types of BRM's, including
retinoids which act directly on cells at the gene expression level, and
thalidomide (and related molecules) which modulate internal circumstances of our body. We have been engaged in medicinal chemical/structural development studies based on these bio-active compounds.
Retinoids include
all-trans-retinoic acid (ATRA), a major active form of
vitamin A (
retinol), and its bio-isosters, which elicit their
biological effects by binding to their
nuclear receptors, RAR's. ATRA has been used in differentiation
therapy [typically for the treatment of
acute promyelocytic leukemia (APL)] and the treatment of dermatological diseases. Our structural development studies of
retinoids, including computer-assisted molecular design has yielded class/subtype-selective agonists, synergists and antagonists of RAR's and their partner
nuclear receptors, RXR's.
Thalidomide elicits a wide range of pharmacological effects, including anti-
cachexia, anti-angiogenic and anti-metastatic activities. We have found that
thalidomide is a multi-target
drug. Hypothetical target events/molecules of
thalidomide include
TNF-alpha production, nuclear
androgen receptor,
aminopeptidases, and
alpha-glucosidase. Specific and potent compounds for each of these target phenomena/molecules have been prepared by appropriate modification of the
thalidomide structure, and are expected to be superior lead compounds for novel
immunomodulators, anti-angiogenic agents, and anti-
tumor promoting agents.