Seiji Nukui

Discovery and stereoselective synthesis of the novel isochroman neurokinin-1 receptor antagonist ‘CJ-17,493’

A novel central nervous system (CNS) selective neurokinin-1 (NK(1)) receptor antagonist, (2S,3S)-3-[(1R)-6-methoxy-1-methyl-1-trifluoromethylisochroman-7-yl]-methylamino-2-phenylpiperidine CJ-17,493 (compound (+)-1), was synthesized stereoselectively using a kinetic resolution by lipase-PS as a key step. Compound (+)-1 displayed high and selective affinity (K(i)=0.2 nM) for the human NK(1) receptor in IM-9 cells, potent activity in the [Sar(9), Met(O(2))(11)]SP-induced gerbil tapping model (ED(50)=0.04 mg/kg, s.c.) and in the ferret cisplatin (10mg/kg, i.p.)-induced anti-emetic activity model (vomiting: ED(90)=0.07 mg/kg, s.c.), all levels of activity comparable with those of CP-122,721. In addition, compound (+)-1 exhibited linear pharmacokinetics rather than the super dose-proportionality of CP-122,721 and this result provides a potential solution for the clinical issue observed with CP-122,721.

Thioether benzenesulfonamide inhibitors of carbonic anhydrases II and IV: Structure-based drug design, synthesis, and biological evaluation

A novel series of potent thioether benzenesulfonamide inhibitors of carbonic anhydrases II and IV was discovered using structure-based drug design. Synthesis, structure-activity relationship, and optimization of physicochemical properties are described. Low nanomolar potency was achieved, and selected compounds with improved thermodynamic solubility showed promising in vitro inhibition of carbonic anhydrase activity in rabbit iris ciliary body homogenate.

Identification of novel pyrrolopyrazoles as protein kinase C β II inhibitors

A novel series of pyrrolopyrazole-based protein kinase C β II inhibitors has been identified from high-throughput screening. Herein, we report our initial structure-activity relationship studies with a focus on optimizing compound ligand efficiency and physicochemical properties, which has led to potent inhibitors with good cell permeability.

Discovery of a novel class of targeted kinase inhibitors that blocks protein kinase C signaling and ameliorates retinal vascular leakage in a diabetic rat model

Protein kinase C (PKC) family members such as PKCbetaII may become activated in the hyperglycemic state associated with diabetes. Preclinical and clinical data implicate aberrant PKC activity in the development of diabetic microvasculature abnormalities. Based on this potential etiological role for PKC in diabetic complications, several therapeutic PKC inhibitors have been investigated in clinical trials for the treatment of diabetic patients. In this report, we present the discovery and preclinical evaluation of a novel class of 3-amino-pyrrolo[3,4-c]pyrazole derivatives as inhibitors of PKC that are structurally distinct from the prototypical indolocarbazole and bisindolylmaleimide PKC inhibitors. From this pyrrolo-pyrazole series, several compounds were identified from biochemical assays as potent, ATP-competitive inhibitors of PKC activity with high specificity for PKC over other protein kinases. These compounds were also found to block PKC signaling activity in multiple cellular functional assays. PF-04577806, a representative from this series, inhibited PKC activity in retinal lysates from diabetic rats stimulated with phorbol myristate acetate. When orally administered, PF-04577806 showed good exposure in the retina of diabetic Long-Evans rats and ameliorated retinal vascular leakage in a streptozotocin-induced diabetic rat model. These novel PKC inhibitors represent a promising new class of targeted protein kinase inhibitors with potential as therapeutic agents for the treatment of patients with diabetic microvascular complications.

4-Chloro-7-hydr­oxy-6-methyl-1,7-naphthyridin-8(7H)-one

The title compound, C9H7ClN2O2, was prepared by reaction of methyl 4-chloro-3-(prop-1-ynyl)picolinate with hydroxylamine in MeOH/KOH solution. The two essentially planar molecules which make up the asymmetric unit have almost identical geometries and and are linked into dimeric aggregates via pairs of O—H⋯O hydrogen bonds. These aggregates have almost perfect inversion symmetry; however, quite unusually, the inversion center of the dimer does not coincide with the crystallographic inversion center.

3-Amino-5-bromo-2-iodo-pyridine.

The reaction of 3-amino-5-bromopyridine with N-iodosuccinimide in the presence of acetic acid produces the title compound, C5H4BrIN, with an iodo substituent in position 2 of the pyridine ring. The crystal structure features rather weak intermolecular N—H⋯N hydrogen bonds linking the molecules into chains along the z axis of the crystal.

6-(2,6-Dimethyl-phen-yl)pyrido[2,3-d]pyrimidin-7-amine.

In the title compound, C15H14N4, the pyrido[2,3-d]pyrimidine system is almost ideally planar (r.m.s. deviation 0.028u2005Å) with its mean plane almost orthogonal to the 2,6-dimethylphenyl plane. The dihedral angle formed by these planes [87.3u2005(2)°] is close to the predicted value (89.7°) obtained by molecular-mechanics force-field calculations. Only one of the two active amine H atoms participates in hydrogen bonding, which links molecules into centrosymmetric dimers.