4 research outputs found
Discovery and Structure–Activity Relationship (SAR) of a Series of Ethanolamine-Based Direct-Acting Agonists of Sphingosine-1-phosphate (S1P<sub>1</sub>)
Sphingosine-1-phosphate
(S1P) is a bioactive sphingolipid metabolite
that regulates a multitude of physiological processes such as lymphocyte
trafficking, cardiac function, vascular development, and inflammation.
Because of the ability of S1P<sub>1</sub> receptor agonists to suppress
lymphocyte egress, they have great potential as therapeutic agents
in a variety of autoimmune diseases. In this article, the discovery
of selective, direct acting S1P<sub>1</sub> agonists utilizing an
ethanolamine scaffold containing a terminal carboxylic acid is described.
Potent S1P<sub>1</sub> agonists such as compounds <b>18a</b> and <b>19a</b> which have greater than 1000-fold selectivity
over S1P<sub>3</sub> are described. These compounds efficiently reduce
blood lymphocyte counts in rats through 24 h after single doses of
1 and 0.3 mpk, respectively. Pharmacodynamic properties of both compounds
are discussed. Compound <b>19a</b> was further studied in two
preclinical models of disease, exhibiting good efficacy in both the
rat adjuvant arthritis model (AA) and the mouse experimental autoimmune
encephalomyelitis model (EAE)
Identification and Preclinical Pharmacology of BMS-986104: A Differentiated S1P<sub>1</sub> Receptor Modulator in Clinical Trials
Clinical
validation of S1P receptor modulation therapy was achieved
with the approval of fingolimod (Gilenya, <b>1</b>) as the first
oral therapy for relapsing remitting multiple sclerosis. However, <b>1</b> causes a dose-dependent reduction in the heart rate (bradycardia),
which occurs within hours after first dose. We disclose the identification
of clinical compound BMS-986104 (<b>3d</b>), a novel S1P<sub>1</sub> receptor modulator, which demonstrates ligand-biased signaling
and differentiates from <b>1</b> in terms of cardiovascular
and pulmonary safety based on preclinical pharmacology while showing
equivalent efficacy in a T-cell transfer colitis model
Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection
The discovery of BMS-605339 (<b>35</b>), a tripeptidic inhibitor of the NS3/4A enzyme, is described.
This compound incorporates a cyclopropylÂacylsulfonamide moiety
that was designed to improve the potency of carboxylic acid prototypes
through the introduction of favorable nonbonding interactions within
the S1′ site of the protease. The identification of <b>35</b> was enabled through the optimization and balance of critical properties
including potency and pharmacokinetics (PK). This was achieved through
modulation of the P2* subsite of the inhibitor which identified the
isoquinoline ring system as a key template for improving PK properties
with further optimization achieved through functionalization. A methoxy
moiety at the C6 position of this isoquinoline ring system proved
to be optimal with respect to potency and PK, thus providing the clinical
compound <b>35</b> which demonstrated antiviral activity in
HCV-infected patients
Identification of a Potent, Selective, and Efficacious Phosphatidylinositol 3‑Kinase δ (PI3Kδ) Inhibitor for the Treatment of Immunological Disorders
PI3Kδ plays an important role
controlling immune cell function and has therefore been identified
as a potential target for the treatment of immunological disorders.
This article highlights our work toward the identification of a potent,
selective, and efficacious PI3Kδ inhibitor. Through careful
SAR, the successful replacement of a polar pyrazole group by a simple
chloro or trifluoromethyl group led to improved Caco-2 permeability,
reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity
profile while maintaining potency in the CD69 hWB assay. The optimization
of the aryl substitution then identified a 4′-CN group that
improved the human/rodent correlation in microsomal metabolic stability.
Our lead molecule is very potent in PK/PD assays and highly efficacious
in a mouse collagen-induced arthritis model