3 research outputs found
Structure-Based Drug Design of Novel Potent and Selective Tetrahydropyrazolo[1,5‑<i>a</i>]pyrazines as ATR Inhibitors
A saturation
strategy focused on improving the selectivity and
physicochemical properties of ATR inhibitor HTS hit <b>1</b> led to a novel series of highly potent and selective tetrahydropyrazolo[1,5-<i>a</i>]pyrazines. Use of PI3Kα mutants as ATR crystal structure
surrogates was instrumental in providing cocrystal structures to guide
the medicinal chemistry designs. Detailed DMPK studies involving cyanide
and GSH as trapping agents during microsomal incubations, in addition
to deuterium-labeled compounds as mechanistic probes uncovered the
molecular basis for the observed CYP3A4 TDI in the series
Structure-Based Drug Design of Novel, Potent, and Selective Azabenzimidazoles (ABI) as ATR Inhibitors
Compound <b>13</b> was discovered
through morphing of the
ATR biochemical HTS hit <b>1</b>. The ABI series was potent
and selective for ATR. Incorporation of a 6-azaindole afforded a marked
increase in cellular potency but was associated with poor PK and hERG
ion channel inhibition. DMPK experiments established that CYP P450
and AO metabolism in conjunction with Pgp and BCRP efflux were major
causative mechanisms for the observed PK. The series also harbored
the CYP3A4 TDI liability driven by the presence of both a morpholine
and an indole moiety. Incorporation of an adjacent fluorine or nitrogen
into the 6-azaindole addressed many of the various medicinal chemistry
issues encountered
Potent Nonimmunosuppressive Cyclophilin Inhibitors With Improved Pharmaceutical Properties and Decreased Transporter Inhibition
Nonimmunosuppressive
cyclophilin inhibitors have demonstrated efficacy
for the treatment of hepatitis C infection (HCV). However, alisporivir,
cyclosporin A, and most other cyclosporins are potent inhibitors of
OATP1B1, MRP2, MDR1, and other important drug transporters. Reduction
of the side chain hydrophobicity of the P4 residue preserves cyclophilin
binding and antiviral potency while decreasing transporter inhibition.
Representative inhibitor <b>33</b> (NIM258) is a less potent
transporter inhibitor relative to previously described cyclosporins,
retains anti-HCV activity in cell culture, and has an acceptable pharmacokinetic
profile in rats and dogs. An X-ray structure of <b>33</b> bound
to rat cyclophilin D is reported