Here's one that begins to describe LGND's extensive androgen program:
S39-2 NOVEL LIGANDS TARGETING THE ANDROGEN RECEPTOR L G Hamann1, J P Edwards1, R I Higuchi1, X N
Wang2, M M Gottardis3, K B Marschke4, W T Schrader3, T K Jones1, 1Medicinal Chemistry, , , , 2Pharmacology, , , ,
3Endocrine Research, , , , 4New Leads Discovery, Ligand Pharmaceuticals, San Diego, CA,
In connection with our program aimed at discovery of androgen receptor (AR) modulators with high tissue specificity, a
molecular approach has been utilized to identify compounds which have the potential to provide unique clinical opportunities
for the treatment of prostate cancer, benign prostatic hypertrophy, alopecia, hirsutism, cachexia, and as male hormone
replacement therapy, without commonly observed side-effects attributable to poor receptor or tissue selectivities. A novel
non-steroidal AR pharmacophore has been discovered using mammalian cell-based cotransfection assays, and investigations
into the structure-activity relationships surrounding this series of molecules has resulted in the identification of two distinct
sub-classes of compounds possessing AR antagonist and agonist activities respectively. Continued intensive preclinical
studies of this pharmacophore, structurally characterized by a linear tricyclic 1,2,3,4-tetrahydro-8-pyridono[5,6-g]quinoline core,
has led to the discovery of highly efficacious compounds with attractive properties.
Compounds from the AR antagonist series inhibit AR-mediated reporter gene expression in the presence of DHT, and bind to
AR as potently or better than any known AR antagonists. Several analogues are also highly efficacious in classic rodent
models of AR antagonism, inhibiting growth of rat ventral prostate, seminal vesicles, and levator ani muscle without
accompanying increases in serum gonadotropin and testosterone levels, as is commonly observed with other known
antiandrogens. Additionally, some of the most potent compounds have further demonstrated high efficacy inhibiting xenograft
tumor growth in the Dunning rat model. Unlike other known antiandrogenic agents, this structural class has very high
specificity for the AR, high peripheral tissue selectivity, and maintains potent in vitro antagonist activity when screened
against an AR mutant commonly found in hormone-refractory prostate cancer patients. Compounds from the AR agonist series
stimulate reporter gene expression in CV-1 and MDA MB-453 cells, and bind to hAR with low nanomolar affinity.
Presentation Date, Time, Room: 26-Jun-98, 3:45P, CC-43
L=Special Session, N=Nurse Symposium, OR=Oral, P=Poster, S=Symposium
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