Genji Iwasaki

A Novel Class of Herbicides (Specific Inhibitors of Imidazoleglycerol Phosphate Dehydratase)

A new mode of herbicidal action was established by finding specific inhibitors of imidazoleglycerol phosphate dehydratase, an enzyme of histidine (His) biosynthesis. Three triazole phosphonates inhibited the reaction of the enzyme with Ki values of 40 [plus or minus] 6.5, 10 [plus or minus] 1.6, and 8.5 [plus or minus] 1.4 nM, respectively, and were highly cytotoxic to cultured plant cells. This effect was completely reversed by the addition of His, proving that the cytotoxicity was primarily caused by the inhibition of His biosynthesis. These inhibitors showed wide-spectrum, postemergent herbicidal activity at application rates ranging from 0.05 to 2 kg/ha.

Discovery of selective and nonpeptidic cathepsin S inhibitors

Nonpeptidic, selective, and potent cathepsin S inhibitors were derived from an in-house pyrrolopyrimidine cathepsin K inhibitor by modification of the P2 and P3 moieties. The pyrrolopyrimidine-based inhibitors show nanomolar inhibition of cathepsin S with over 100-fold selectivity against other cysteine proteases, including cathepsin K and L. Some of the inhibitors showed cellular activities in mouse splenocytes as well as oral bioavailabilities in rats.

Discovery of Orally Bioavailable Cathepsin S Inhibitors for the Reversal of Neuropathic Pain

Cathepsin S inhibitors are well-known to be an attractive target as immunological therapeutic agents. Recently, our gene expression analysis identified that cathepsin S inhibitors could also be effective for neuropathic pain. Herein, we describe the efficacy of selective cathepsin S inhibitors as antihyperalgesics in a model of neuropathic pain in rats after oral administration.

Discovery of IRL 3461: a novel and potent endothelin antagonist with balanced ETA/ETB affinity

IRL 3461, N-butanesulfonyl-[N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-+ ++isoxazolyl) -phenyl]-alanyl]-(L)-valineamide, a potent and bifunctional (ETA + ETB) [Ki(ETA) = 1.8 nM, Ki(ETB) = 1.2 nM] antagonist was discovered by structural modification of IRL 2500, an ETB selective antagonist. IRL 3461 was found to be stable on incubation with human, rat, mouse, and guinea pig plasmas.

Overcoming hERG issues for brain-penetrating cathepsin S inhibitors: 2-cyanopyrimidines. Part 2.

We describe here orally active and brain-penetrant cathepsin S selective inhibitors, which are virtually devoid of hERG K(+) channel affinity, yet exhibit nanomolar potency against cathepsin S and over 100-fold selectivity to cathepsin L. The new non-peptidic inhibitors are based on a 2-cyanopyrimidine scaffold bearing a spiro[3.5]non-6-yl-methyl amine at the 4-position. The brain-penetrating cathepsin S inhibitors demonstrate potential clinical utility for the treatment of multiple sclerosis and neuropathic pain.

Effect of Cathepsin K Inhibitors on Bone Resorption

On the basis of the pyrrolopyrimidine core structure that was previously discovered, cathepsin K inhibitors having a spiro amine at the P3 have been explored to enhance the target, bone marrow, tissue distribution. Several spiro structures were identified with improved distribution toward bone marrow. The representative inhibitor 7 of this series revealed in vivo reduction in C-terminal telopeptide of type I collagen in rats and monkeys.

4-Amino-2-cyanopyrimidines: Novel scaffold for nonpeptidic cathepsin S inhibitors

We describe here a novel 4-amino-2-cyanopyrimidine scaffold for nonpeptidomimetic cathepsin S selective inhibitors. Some of the synthesized compounds have sub-nanomolar potency and high selectivity toward cathepsin S along with promising pharmacokinetic and physicochemical properties. The key structural features of the inhibitors consist of a combination of a spiro[2.5]oct-6-ylmethylamine P2 group at the 4-position, a small or polar P3 group at the 5-position and/or a polar group at the 6-position of the pyrimidine.

Trimethylsilyl triflate promoted 1,4-addition of silyl phosphites to cyclic enones

Abstract A catalytic amount of trimethylsilyl triflate (TMSOTf) remarkably facilitates the selective conjugate addition of a variety of silyl phosphites, prepared in situ from dialkyl phosphites and N , O -bis(trimethylsilyl)acetamide, to cyclic enones giving 1,4-adducts in high yields.

New chemotypes for cathepsin K inhibitors

Cyano pyrimidine acetylene and cyano pyrimidine t-amine, which belong to a new chemical class, were prepared and tested for inhibitory activities against cathepsin K and the highly homologous cathepsins L and S. The use of novel chemotypes in the development of cathepsin K inhibitors has been demonstrated by derivatives of compounds 1 and 8.

Computational modeling of a binding conformation of the intermediate L-histidinal to histidinol dehydrogenase.

Histidinol dehydrogenase (HDH) is one of the enzymes involved in the L-histidine biosynthesis pathway. HDH is a dimer that contains one Zn2+ ion in each identical subunit. In this study, we predicted a possible binding conformation of the intermediate L-histidinal, which is experimentally not known, using a computational modeling method and three potent HDH inhibitors whose structures are similar to that of L-histidinal. At first, a set of the most probable active conformations of the potent inhibitors was determined using two different pharmacophore mapping techniques, the active analogue approach and the distance comparison method. From the most probable active conformations of the three potent inhibitors, the common parts of the L-histidinal structure were extracted and refined by energy minimization to obtain the binding conformation of L-histidinal. This predicted conformation of L-histidinal agrees with an experimentally determined conformation of L-histidine in a single crystal, suggesting that it is an experimentally acceptable conformation. The capability in this conformation to coordinate a Zn2+ ion was examined by comparing the spatial relative geometry of its functional groups with those of ligands that coordinate with a Zn2+ ion in Zn proteins of the Protein Data Bank. This comparison supported our predicted conformation.