The Scripps Research Institute

Hoffmann-la Roche Inc.

William Marsh Rice University

Anadys Pharmaceuticals, Inc.

Dionisios Vourloumis

Kyriacos Costa Nicolaou

Yun He

Frank Roschangar

Hans Vallberg

Sacha Ninkovic

Nicolas Winssinger

Nigel Paul King

Francisco Sarabia

Douglas Eric Murphy

Zhen Yang

M Ray Finlay

Joaquin Pastor

Chinh Viet Tran

Maurice Raymond Verschoyle Finlay

Robert Francis Kester

Antony Bigot

Frank Ruebsam

Steven Joseph Berthel

Tianhu Li

N Paul King

Rohan Diliprao Erande

Thomas Jay Prins

Ramakanth Sarabu

Vlad Edward Gregor

Debashis Mandal

Yuefen Zhou

Klaus B Simonsen

Zhongxiang Sun

Thomas C Hermann

Kiran Kumar Pulukuri

Stephan Rigol

David Hepworth

Jin-You Xu

Jeff Pfefferkorn

Takashi Ohshima

Sanghee Kim

Jun Yin

Seijiro Hosokawa

Floris VanDelft

Phillipp Klahn

Geoffrey C Winters

Benjamin Ayida

Maruice Raymond Verschoyle Finlay

In one aspect, the present disclosure provides tubulysin analogs of the formula (I) wherein the variables are as defined herein. In another aspect, the present disclosure also provides methods of preparing the compounds disclosed herein. In another aspect, the present disclosure also provides pharmaceutical compositions and methods of use of the compounds disclosed herein. Additionally, drug conjugates with cell targeting moieties of the compounds are also provided. 

Tubulysin analogues as anticancer agents and payloads for antibody-drug conjugates and methods of treatment therewith

In one aspect, the present disclosure provides tubulysin analogs of the formula (I) wherein R, R, R, R, X, X, X, and Aare as defined herein. In another aspect, the present disclosure also provides methods of preparing the compounds disclosed herein. In another aspect, the present disclosure also provides pharmaceutical compositions and methods of use of the compounds disclosed herein. 

Desacetoxytubulysin H and analogs thereof

Disclosed herein are pyrazole glucokinase activators of the formula (I) useful for the treatment of metabolic diseases and disorders, preferably diabetes mellitus.

Pyrazole glucokinase activators

Disclosed herein are pyrazole glucokinase activators of the formula (I): that are useful for the treatment of metabolic diseases and disorders.

Oxime glucokinase activators

The invention relates to epothilone analog represented by the formula I wherein(i) Ris absent or oxygen; 'a' can be either a single or double bond; 'b' can be either absent or a single bond; and &#x201c;c&#x201d; can be either absent or a single bond, with the proviso that if Ris oxygen then &#x201c;b&#x201d; and &#x201c;c&#x201d; are both a single bond and &#x201c;a&#x201d; is a single bond; if Ris absent then &#x201c;b&#x201d; and &#x201c;c&#x201d; are absent and &#x201c;a&#x201d; is a double bond; and if &#x201c;a&#x201d; is a double bond, then R, &#x201c;b&#x201d; and &#x201c;c&#x201d; are absent; These compounds have inter alia microtubuli depolymerisation inhibiting activity and are e.g. useful against proliferative diseases.

Epothilone derivatives and their synthesis and use

The invention relates to antibacterial 3,5-diaminopiperidine-substituted aromatic and heteroaromatic compounds and pharmaceutical compositions thereof. This invention also relates to a method of using such compounds in the treatment of bacterial infections in mammals, especially humans.

Antibacterial 3,5-diaminopiperidine-substituted aromatic and heteroaromatic compounds

Epothilone A, epothilone B, analogs of epothilone and libraries of epothilone analogs are synthesized. Epothilone A and B are known anticancers agents that derive their anticancer activity by the prevention of mitosis through the induction and stabilization of microtubulin assembly. The analogs of epothilone are novel. Several of the analogs are demonstrated to have a superior cytotoxic activity as compared to epothilone A or epothilone B as demonstrated by their enhanced ability to induce the polymerization and stabilization of microtubules.

Epothilone analogs

Epothilone A, epothilone B, analogs of epothilone and libraries of epothilone analogs are synthesized. Epothilone A and B are known anticancers agents that derive their anticancer activity by the prevention of mitosis through the induction and stabilization of microtubule assembly. The analogs of epothilone are novel. Several of the analogs are demonstrated to have a superior cytotoxic activity as compared to epothilone A or epothilone B as demonstrated by their enhanced ability to induce the polymerization and stabilization of microtubules.

The invention relates to epothilone analog represented by formula (I) wherein (i) R is absent or oxygen; &ldquo;a&rdquo; can be either a single or double bond; &ldquo;b&rdquo; can be either absent or a single bond; and &ldquo;c&rdquo; can be either absent or a single bond, with the proviso that if R is oxygen then &ldquo;b&rdquo; and &ldquo;c&rdquo; are both a single bond and &ldquo;a&rdquo; is a single bond; if R is absent then &ldquo;b&rdquo; and &ldquo;c&rdquo; are absent and &ldquo;a&rdquo; is a double bond; and if &ldquo;a&rdquo; is a double bond, then R , &ldquo;b&rdquo; and &ldquo;c&rdquo; are absent; R is a radical selected from the group consisting of hydrogen; lower alkyl; &mdash;CH&boxH;CH ; &mdash;C&equiv;CH; &mdash;CH F; &mdash;CH Cl; &mdash;CH &mdash;OH; &mdash;CH &mdash;O&mdash;(C -C -alkyl); and &mdash;CH &mdash;S&mdash;(C -C -alkyl); R and R are independently selected from hydrogen, methyl or a protecting group; and R is as defined in the specification, or a salt of a compound of formula (I) where a salt-forming group is present. A further aspect of the invention is related to the synthesis of epothilone E. These compounds have inter alia microtubuli depolymerization inhibiting activity and are e.g. useful against proliferative diseases

Epothilone A, epothilone B, analogs of epothilone and libraries of epothilone analogs are synthesized. Epothilone A and B are known anticancer agents that derive their anticancer activity by the prevention of mitosis through the induction and stabilization of microtubulin assembly. The analogs of epothilone are novel. Several of the anlogs are demonstrated to have a superior cytotoxic activities as compared to epothilone A or epothilone B as demonstrated by their enhanced ability to induce the polymerization and stabilization of microtubules.

Novel analogs of epothilone A, epothilone B, and epothilone C are synthesized by Stille coupling thazole-stannanes to macrolactone intermediates. The synthetic epothilone analogs selectively prevent mitosis in cancer cells through the induction and stabilization of microtubulin assembly. Selected synthetic epothilone analogs are demonstrated to have greater bioactivity than their corresponding native compound.

Sarcodictyin A and B, eleutherobin, and bioactive analogs thereof synthesized using solid phase and solution phase chemistries. The synthetic method employs an attachment of common precursors, e.g., compounds 1880 or 200, on a solid support for generating conjugates 230 and 240, followed by standard chemical manipulations. A combinatorial library of sarcodictyins and eletherobin analogs was constructed with modified C-8 ester, C-15 ester and C-4 ketal functionalities and was screened for activity with respect to tubulin polymerization and cytotoxic activity against tumor cells, including Taxol-resistant lines. Compounds 600, 610, 630, 660-700, 730, 760, 850, and 920 were identified to be of equal or superior biological activities as compared to their corresponding natural product.

Analogs of sarcodictyin and eleutherobin

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Athens, Greece

Dionisios Vourloumis