Takeda Pharmaceutical Company Limited

Haruhide Kimura

Masahiro Kajino

Yutaka Nakayama

Taisuke Tawaraishi

Akira Kawada

Satoru Matsuda

Emi Kurimoto

Yoshimi Sato

Yuji Shimizu

Yuu Sako

Masayauki Takizawa

Takao Mandai

The present invention provides a useful and efficient screening method for finding a cholinergic muscarinic M1 receptor positive allosteric modulator (M1PAM) with reduced cholinergic side effects. The present invention also provides a method for treating Alzheimer's disease and the like, a method for reducing cholinergic side effects, and the like which use M1PAM selected by the screening method and having a low α value, or the M1PAM and an acetylcholinesterase inhibitor.

Method for measuring alpha value of muscarinic M1 receptor positive allosteric modulators

The present invention relates to an antioxidant response element (ARE) activator comprising a macrophage migration inhibitory factor (MIF) or a modified form thereof, an ARE activator comprising a combination of MIF or a modified form thereof and a substance capable of binding to MIF, such as a 1,3-benzothiazinone, and so on. These ARE activators are useful.

Cell death inhibition by macrophage migration inhibitory factor and a binding substance thereto

The invention provides a screening method and screening kit for a cell protecting agent. Specifically, the invention provides a method for screening a cell protecting agent showing an Hsp90-binding activity and a heat shock protein expression-inducing activity but having no Hsp90 client protein degradation-promoting activity. The method comprises the following steps (1) to (3): (1) measuring the binding property of a test compound to Hsp90; (2) measuring the activity of a test compound to induce the expression of a heat shock protein, or measuring the activity of a test compound to disrupt an Hsp90/HSF-1 complex, by using a cell capable of expressing the heat shock protein; and (3) measuring the activity of a test compound to induce the degradation of an Hsp90 client protein by using a cell capable of expressing the Hsp90 client protein. The invention further provides specifically a kit for screening a cell protecting agent, comprising (1) Hsp90; (2) a reagent for measuring the heat shock protein expression-inducing activity; (3) an imidazothiazine derivative; and (4) a reagent for quantifying an Hsp90 client protein.

Method for screening of cell-protecting agent

The cell death inhibitor comprising a substance capable of binding to macrophage migration inhibitory factor is useful as a preventive/therapeutic agent for, e.g., heart diseases, neurodegenerative diseases, cerebrovascular diseases, central nervous infections, traumatic diseases, demyelinating diseases, bone/joint diseases, kidney diseases, liver diseases, myelodysplastic diseases, arteriosclerosis, diabetes, pulmonary hypertension, sepsis, inflammatory bowel diseases, autoimmune diseases, failure accompanying rejection in organ transplantation, AIDS, cancer, etc.

Cell death inhibitor

This invention provides a compound represented by the formula (I): wherein Ris a hydrogen atom, a halogen atom, hydroxy, nitro, optionally halogenated alkyl, alkoxy optionally having substituents, acyl or amino optionally having substituents;Ris pyridyl, furyl, thienyl, pyrrolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, tetrahydroquinolyl or thiazolyl, each of which may have substituents;n is 1 or 2; or a salt. And this invention provides a safe pharmaceutical comprising the compound of the formula (I), which has an excellent apoptosis inhibitory effect and MIF binding effect, for preventing and/or treating heart disease, nervous degenerative disease, cerebrovascular disease, central nervous infectious disease, traumatorathy, demyelinating disease, bone and articular disease, kidney disease, liver disease, osteomyelodysplasia, AIDS, cancer, and the like.

1,3-benzothiazinone derivatives and use thereof

As prophylactic and/or therapeutic agents for cardiovascular diseases, bone or joint diseases, infectious diseases, inflammatory diseases, kidney diseases, etc. having safe and excellent effects of cell death inhibition, MIF binding, etc., there are provided compounds represented by formula: [wherein, Rrepresents a halogen atom, etc., Rrepresents a group represented by formula: (wherein, Rrepresents hydrogen atom, an optionally substituted alkoxy, etc., Rrepresents hydrogen atom, bromine atom, cyano, etc., Rrepresents hydrogen atom, hydroxy, etc., Rrepresents hydrogen atom, etc., Rrepresents hydrogen atom, etc.) etc., and n represents an integer of 0 to 4] or salts thereof.

1,3-Benzothiazinone derivatives, process for producing the same use thereof

This invention provides a compound represented by the formula (I): wherein Ris a hydrogen atom, a halogen atom, hydroxy, nitro, optionally halogenated alkyl, alkoxy optionally having substituents, acyl or amino optionally having substituents; Ris pyridyl, furyl, thienyl, pyrrolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, tetrahydroquinolyl or thiazolyl, each of which may have substituents; n is 1 or 2; or a salt. And this invention provides a safe pharmaceutical comprising the compound of the formula (I), which has an excellent apoptosis inhibitory effect and MIF binding effect, for preventing and/or treating heart disease, nervous degenerative disease, cerebrovascular disease, central nervous infectious disease, traumatorathy, demyelinating disease, bone and articular disease, kidney disease, liver disease, osteomyelodysplasia, AIDS, cancer, and the like.

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Osaka, Japan

Haruhide Kimura