Large macrocyclic peptides can achieve surprisingly high membrane permeability,a lthough the properties that govern permeability in this chemical space are only beginning to come into focus.W eg enerated two libraries of cyclic decapeptides with stable cross-b conformations,and found that peptoid substitutions within the b-turns of the macrocycle preserved the rigidity of the parent scaffold, whereas peptoid substitutions in the opposing b-strands led to "chameleonic" species that were rigid in nonpolar media but highly flexible in water.B oth rigid and chameleonic compounds showed high permeability over aw ide lipophilicity range,w ith peak permeabilities differing significantly depending on scaffold rigidity.Our findings indicate that modulating lipophilicity can be used to engineer favorable ADME properties into both rigid and flexible macrocyclic peptides,and that scaffold rigidity can be used to tune optimal lipophilicity.
Large macrocyclic peptides can achieve surprisingly high membrane permeability,a lthough the properties that govern permeability in this chemical space are only beginning to come into focus.W eg enerated two libraries of cyclic decapeptides with stable cross-b conformations,and found that peptoid substitutions within the b-turns of the macrocycle preserved the rigidity of the parent scaffold, whereas peptoid substitutions in the opposing b-strands led to "chameleonic" species that were rigid in nonpolar media but highly flexible in water.B oth rigid and chameleonic compounds showed high permeability over aw ide lipophilicity range,w ith peak permeabilities differing significantly depending on scaffold rigidity.Our findings indicate that modulating lipophilicity can be used to engineer favorable ADME properties into both rigid and flexible macrocyclic peptides,and that scaffold rigidity can be used to tune optimal lipophilicity.
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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