Abstract. A pyrazolone compound acting as a formyl peptide receptor (FPR) 2/ALX-selective agonist has been reported, but its pharmacological activities on human FPRs (hFPRs) and mouse FPRs (mFprs) have not been well demonstrated. In this study, we found that this compound, designated as compound A, induced concentration-dependent calcium flux not only in Chinese hamster ovary (CHO) cells expressing hFPR2/ALX but also in cells expressing hFPR1, mFpr1, or mFpr2. It also induced the receptor internalization of hFPR1 and hFPR2/ ALX and, accordingly, induced calcium influx and chemotactic responses in both human and mouse neutrophils. Our study revealed that compound A is in fact an FPR1 and FPR2/ALX dual agonist.
A highly
potent, selective NaV1.7 inhibitor, DS-1971a,
has been discovered. Exploration of the left-hand phenyl ring of sulfonamide
derivatives (I and II) led to the discovery
of novel series of cycloalkane derivatives with high NaV1.7 inhibitory potency in vitro. As the right-hand heteroaromatic
ring affected the mechanism-based inhibition liability of CYP3A4,
replacement of this moiety resulted in the generation of 4-pyrimidyl
derivatives. Additionally, GSH adducts formation, which can cause
idiosyncratic drug toxicity, was successfully avoided by this modification.
An additional optimization led to the discovery of DS-1971a. In preclinical
studies, DS-1971a demonstrated highly potent selective in vitro profile
with robust efficacy in vivo. DS-1971a exhibited a favorable toxicological
profile, which enabled multiple-dose studies of up to 600 mg bid or
400 mg tid (1200 mg/day) administered for 14 days to healthy human
males. DS-1971a is expected to exert potent efficacy in patients with
peripheral neuropathic pain, with a favorable safety profile.
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