Novartis Ag

Kyowa Hakko Kirin Co., Limited

Hidetomo Imase

Qi-Ying Hu

Yuki Iwaki

Kayo Yasoshima

Ichiro Umemura

Muneto Mogi

Toshio Kawanami

Ken Yamada

Hongjuan Zhao

Andrei Alexandrovich Golosov

Osamu Ohmori

Hongbo Qin

Frederic Zecri

Philipp Grosche

Naoko Matsuura

Eiji Kawahara

Masashi Kishida

Yoshisuke Nakasato

Julien Papillon

David Thomas Parker

Sylvie Chamoin

Takahiro Miyake

Frédéric Zecri

Martin Allan

Philippr Grosche

Kuniyuki Kishikawa

Hajime Kashima

Kiyotoshi Mori

Toshihide Ikemura

Misato Tomuro

The invention provides methods to prepare protein conjugates from proteins having at least two cysteines. In one embodiment, a protein with a disulfide linkage is reduced to provide two free cysteines for reaction with a 1,3-dihaloacetone or similar reactant, linking the sulfur atoms of the two cysteines together. The ketone inserted between the sulfur atoms is then used to form a Schiff base to an aminated payload molecule, thus conjugating the protein to a payload. In another embodiment, two cysteine residues are tied together by reaction with a 1,3-dihaloacetone or similar reactant. The linkage between the sulfur atoms in each case holds the protein or peptide in a constrained conformation, while also providing a convenient place for attaching a payload with good specificity and efficiency.

Methods for making conjugates from disulfide-containing proteins

The invention provides improved methods to prepare protein conjugates from a ketone-modified protein. In one embodiment, the protein is prepared by linking two free cysteines by reaction with a 1,3-dihaloacetone or similar ketone-containing reactant, linking the sulfur atoms of the two cysteines together. The ketone inserted between the sulfur atoms is then used to form an oxime, thus conjugating the protein to a payload. In another embodiment, two cysteine residues are tied together by reaction with a 1,3-dihaloacetone or similar reactant, and the new ketone is used to form an oxime with a suitable payload molecule, thus conjugating the protein to a payload. The method provides improved reaction conditions for the oxime formation, whereby higher yields and improved product homogeneity are achieved.

Methods for oxime conjugation to ketone-modified polypeptides

The invention provides a synthetic polypeptide of Formula I': 

Synthetic apelin mimetics for the treatment of heart failure

The present invention provides a compound of formula (I): wherein the variants R1, R2, R3, R4, R6, R7 are as defined herein, and wherein said compound is an inhibitor of CETP, and thus can be employed for the treatment of a disorder or disease mediated by CETP or responsive to the inhibition of CETP. 

Organic compounds

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R, R, R, R, Rand n are defined herein. The invention also relates to a method for manufacturing compounds of the invention, and their therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition. 

Aryl-pyridine derivatives as aldosterone synthase inhibitors

The present invention provides a compound of formula (I): wherein the variants R1, R2, R3, R4, R5, R6, R7 are as defined herein, and wherein said compound is an inhibitor of CETP, and thus can be employed for the treatment of a disorder or disease mediated by CETP or responsive to the inhibition of CETP.

4-benzylamino-1-carboxylacyl-piperidine derivatives as CETP inhibitors

Method of inhibiting CETP activity with 4-benzylamino-1-carboxylacyl-piperidine derivatives

The present invention relates to novel compounds of formula (I) or a pharmaceutical composition thereof, with all the variables being defined in the text. The present invention further relates to the use of the compounds herein for treatment of or delay progression to overt to diseases in which CETP is involved.

Bicyclic derivatives as CETP inhibitors

The present invention provides 2-aminoquinazoline derivatives represented by formula (I): 

2-aminoquinazoline derivatives

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Somerville, MA, United States of America

Hidetomo Imase