Theravance, Inc.

The General Hospital Corporation

Theravance Biopharma R&d Ip, LLC

Yuhua Ji

YongQi Mu

Craig Husfeld

Mathai Mammen

Li Li

Rick Andrew Lee

Eric L Stangeland

Adam D Hughes

Viengkham Malathong

Christopher W Lange

Cameron Smith

Trevor Mischki

Aaron Kushner

Johnny Uy

Sarah Dunham

Vamsi K Mootha

Sunil A Sheth

Vishal Gohil

Model systems have shown that shifting a cell's reliance from oxidative phosphorylation (OXPHOS) to glycolysis can protect against cell death. Exploiting the therapeutic potential of this strategy, however, has been limited by the lack of clinically safe agents that remodel energy metabolism. The present invention identifies non-toxic small molecules (e.g., drug-like compounds) that are capable of modulating oxidative metabolism. One identified compound comprises meclizine. As described herein, meclizine, and its enantiomer S-meclizine, redirects OXPHOS to glycolysis. Such compounds could be protective or therapeutic in degenerative disorders such as diabetes, Huntington's, Parkinson's, and Alzheimer's disease and/or ischemic disorders including, but not limited to, stroke, heart attack, or reperfusion injuries.

Methods and compositions for treating degenerative and ischemic disorders

The invention provides compounds of the formula: in salt or zwitterionic form or a pharmaceutically acceptable salt thereof, wherein R, a, Z and Q are as defined in the specification. These compounds are muscarinic receptor antagonists. The invention also provides pharmaceutical compositions containing such compounds, processes for preparing such compounds and methods of using such compounds to, for example, treat pulmonary disorders such as chronic obstructive pulmonary disease and asthma.

Quaternary ammonium compounds useful as muscarinic receptor antagonists

The invention provides compounds of formula I: in salt or zwitterionic form or a pharmaceutically acceptable salt thereof, wherein R, a-e and Q are as defined in the specification. These compounds are muscarinic receptor antagonists. The invention also provides pharmaceutical compositions containing such compounds, processes for preparing such compounds and methods of using such compounds to, for example, treat pulmonary disorders such as chronic obstructive pulmonary disease and asthma.

Quaternary ammonium diphenylmethyl compounds useful as muscarinic receptor antagonists

This invention provides compounds of formula I: wherein a, b, c, d, m, n, p, s, t, W, Ar, R, R, R, R, R, R, and Rare as defined in the specification. The compounds of formula I are muscarinic receptor antagonists. The invention also provides pharmaceutical compositions containing such compounds, processes and intermediates for preparing such compounds and methods of using such compounds to treat pulmonary disorders.

Biphenyl compounds useful as muscarinic receptor antagonists

The invention provides compounds of formula I: wherein a, b, c, d, n, R, R, R, R, R, W, and A are as defined in the specification. The compounds of formula I are muscarinic receptor antagonists. The invention also provides pharmaceutical compositions containing such compounds, processes and intermediates for preparing such compounds and methods of using such compounds to treat pulmonary disorders.

The invention provides compounds of formula I: wherein a, b, c, m, n, q, r, W, Z, Ar, Z, Y, R, R, and Rare as defined in the specification. The compounds of formula I are muscarinic receptor antagonists. The invention also provides pharmaceutical compositions containing such compounds, processes and intermediates for preparing such compounds and methods of using such compounds to treat pulmonary disorders.

The invention relates to compounds of formula I: or a pharmaceutically acceptable salt thereof, where R, R, R, a, b, Q, X, X', X&#x2033;, Y, Z, and Ar are as defined in the specification. These compounds are muscarinic receptor antagonists. The invention also relates to pharmaceutical compositions containing such compounds, processes for preparing such compounds and methods of using such compounds to, for example, treat pulmonary disorders such as chronic obstructive pulmonary disease and asthma.

Amidine-containing compounds useful as muscarinic receptor antagonists

The invention provides compounds of formula I: wherein a, b, c, m, s, t, W, Z, Ar, R, R, R, R, and Rare as defined in the specification. The compounds of formula I are muscarinic receptor antagonists. The invention also provides pharmaceutical compositions containing such compounds, processes and intermediates for preparing such compounds and methods of using such compounds to treat pulmonary disorders.

The invention provides compounds of formula I: or a pharmaceutically acceptable salt thereof, wherein R, R, a, X, Y, Y', Y&#x2033;, and Z are as defined in the specification. These compounds are muscarinic receptor antagonists. The invention also provides pharmaceutical compositions containing such compounds, processes for preparing such compounds and methods of using such compounds to, for example, treat pulmonary disorders such as chronic obstructive pulmonary disease and asthma.

Guanidine-containing compounds useful as muscarinic receptor antagonists

The invention provides compounds of formula I: wherein a, b, c, p, W, A, X, R, R, R, R, R, and Rare as defined in the specification. The compounds of formula I are muscarinic receptor antagonists. The invention also provides pharmaceutical compositions containing such compounds, processes and intermediates for preparing such compounds and methods of using such compounds to treat pulmonary disorders.

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Redwood City, CA, United States of America

Yuhua Ji