2 research outputs found
Discovery of the Selective CYP17A1 Lyase Inhibitor BMS-351 for the Treatment of Prostate Cancer
Efforts to identify a potent, reversible,
nonsteroidal CYP17A1
lyase inhibitor with good selectivity over CYP17A1 hydroxylase and
CYPs 11B1 and 21A2 for the treatment of castration-resistant prostate
cancer (CRPC) culminated in the discovery of BMS-351 (compound <b>18</b>), a pyridyl biaryl benzimidazole with an excellent <i>in vivo</i> profile. Biological evaluation of BMS-351 at a dose
of 1.5 mg in castrated cynomolgus monkeys revealed a remarkable reduction
in testosterone levels with minimal glucocorticoid and mineralcorticoid
perturbation. Based on a favorable profile, BMS-351 was selected as
a candidate for further preclinical evaluation
Identification of Tricyclic Agonists of Sphingosine-1-phosphate Receptor 1 (S1P<sub>1</sub>) Employing Ligand-Based Drug Design
Fingolimod (<b>1</b>) is the
first approved oral therapy
for the treatment of relapsing remitting multiple sclerosis. While
the phosphorylated metabolite of fingolimod was found to be a nonselective
S1P receptor agonist, agonism specifically of S1P<sub>1</sub> is responsible
for the peripheral blood lymphopenia believed to be key to its efficacy.
Identification of modulators that maintain activity on S1P<sub>1</sub> while sparing activity on other S1P receptors could offer equivalent
efficacy with reduced liabilities. We disclose in this paper a ligand-based
drug design approach that led to the discovery of a series of potent
tricyclic agonists of S1P<sub>1</sub> with selectivity over S1P<sub>3</sub> and were efficacious in a pharmacodynamic model of suppression
of circulating lymphocytes. Compound <b>10</b> had the desired
pharmacokinetic (PK) and pharmacodynamic (PD) profile and demonstrated
maximal efficacy when administered orally in a rat adjuvant arthritis
model