Yoshisuke Nakayama

Non-peptidic inhibitors of human neutrophil elastase: The design and synthesis of sulfonanilide-containing inhibitors

A novel series of pivaloyloxy benzene derivatives has been identified as potent and selective human neutrophil elastase (HNE) inhibitors. Convergent syntheses were developed in order to identify the inhibitors which are intravenously effective in an animal model. A compound of particular interest is the sulfonanilide-containing analogues. Structure-activity relationships are discussed. Structural requirements for metabolic stabilization are also discussed.

New serine protease inhibitors with leukotriene B4 (LTB4) receptor binding affinity

A series of new trypsin-like serine protease inhibitors, 1, 2 and 7-23, containing amidinobenzene moiety was found to show potent LTB4-receptor affinity. Among them, compounds 1 and 2 were found to be LTB4 receptor antagonists based on an inhibition assay of human polymorphonuclear neutrophil (PMN) intracellular calcium mobilization induced by LTB4. Compounds 1 and 2, which satisfy the reported structural requirements for good oral activity, are expected to show a balanced dual mode of action, i.e., protease inhibitory activity and LTB4 receptor antagonist activity, in vivo.

Discovery of Gemilukast (ONO-6950), a Dual CysLT1 and CysLT2 Antagonist As a Therapeutic Agent for Asthma.

An orally active dual CysLT1 and CysLT2 antagonist possessing a distinctive structure which consists of triple bond and dicarboxylic acid moieties is described. Gemilukast (ONO-6950) was generated via isomerization of the core indole and the incorporation of a triple bond into a lead compound. Gemilukast exhibited antagonist activities with IC50 values of 1.7 and 25 nM against human CysLT1 and human CysLT2, respectively, and potent efficacy at an oral dose of 0.1 mg/kg given 24 h before LTD4 challenge in a CysLT1-dependent guinea pig asthmatic model. In addition, gemilukast dose-dependently reduced LTC4-induced bronchoconstriction in both CysLT1- and CysLT2-dependent guinea pig asthmatic models, and it reduced antigen-induced constriction of isolated human bronchi. Gemilukast is currently being evaluated in phase II trials for the treatment of asthma.

Discovery of a potent, orally available dual CysLT1 and CysLT2 antagonist with dicarboxylic acid

A potent, orally available dual CysLT₁ and CysLT₂ receptor antagonist with a dicarboxylic acid is described. 4-(3-(Carboxymethyl)-4-{(E)-2-[4-(4-phenoxybutoxy)phenyl]vinyl}-1H-indol-1-yl)butanoic acid (15: ONO-4310321, IC₅₀: CysLT₁=13nM, CysLT₂=25 nM) showed excellent pharmacokinetic profiles (%Frat=100) compared with our previously reported compound 1 (%Frat=1.5). In addition, we describe a new rule for dicarboxylic acid derivatives to show good oral bioavailability (%Frat⩾40) in rats (HBDs: ⩽2, ClogP: >6.5 and TPSA: <100). Especially, reduction of only one hydrogen-bond donor (HBDs) showed dramatically improved oral bioavailability. This small change of HBDs in dicarboxylic acid derivatives is generally a very effective modification.

Discovery of Highly Potent Dual CysLT1 and CysLT2 Antagonist.

The benzoxazine derivative, (2S)-4-(3-carboxypropyl)-8-{[4-(4-phenylbutoxy)benzoyl]amino}-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (19, ONO-2050297), was identified as the first potent dual CysLT1 and CysLT2 antagonist with IC50 values of 0.017 μM (CysLT1) and 0.00087 μM (CysLT2), respectively.