Molecular hybridization yields triazole bronchodilators for the treatment of COPD.

A 1,2,4-triazole motif was employed as a bioisostere for the ester commonly used in muscarinic antagonists, and subsequent integrative conjugation to a ß2 agonist quinolinone furnished a new class of bifunctional MABAs for the treatment of COPD. Medicinal chemistry optimization using the principles of 'inhalation by design' furnished a clinical candidate with desirable pharmacological, pharmacokinetic and biopharmaceutical properties.

Discovery of a Selective TRPM8 Antagonist with Clinical Efficacy in Cold-Related Pain.

The transient receptor potential (TRP) family of ion channels comprises nonselective cation channels that respond to a wide range of chemical and thermal stimuli. TRPM8, a member of the melastatin subfamily, is activated by cold temperatures (<28 °C), and antagonists of this channel have the potential to treat cold induced allodynia and hyperalgesia. However, TRPM8 has also been implicated in mammalian thermoregulation and antagonists have the potential to induce hypothermia in patients. We report herein the identification and optimization of a series of TRPM8 antagonists that ultimately led to the discovery of PF-05105679. The clinical finding with this compound will be discussed, including both efficacy and its ability to affect thermoregulation processes in humans.

A perspective on synthetic and solid-form enablement of inhalation candidates.

The administration of compounds by a dry-powder inhaler presents significant challenges to the development and discovery chemist, owing to the stringent requirements placed upon the physical characteristics of the active pharmaceutical ingredient and the high complexity of the molecules concerned. The current state of synthetic chemistry technology is such that commercial syntheses of these compounds are demanding but achievable. While synthetic chemistry will remain a major component of the development of inhaled therapies, the main challenge facing practitioners in this area is the early identification of a suitable solid form. Further advances in the prediction of solid-form properties would significantly enable this field and may allow triage of molecules to be carried out at the design stage of projects.

Inhalation by design: novel tertiary amine muscarinic M3 receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease.

A novel tertiary amine series of potent muscarinic M(3) receptor antagonists are described that exhibit potential as inhaled long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease. Geminal dimethyl functionality present in this series of compounds confers very long dissociative half-life (slow off-rate) from the M(3) receptor that mediates very long-lasting smooth muscle relaxation in guinea pig tracheal strips. Optimization of pharmacokinetic properties was achieved by combining rapid oxidative clearance with targeted introduction of a phenolic moiety to secure rapid glucuronidation. Together, these attributes minimize systemic exposure following inhalation, mitigate potential drug-drug interactions, and reduce systemically mediated adverse events. Compound 47 (PF-3635659) is identified as a Phase II clinical candidate from this series with in vivo duration of action studies confirming its potential for once-daily use in humans.

A highly selective method for 11 beta-OH protection of steroidal 11 beta, 17 alpha-diols.

A highly selective method to protect the 11 beta-OH position of steroid (1) has been developed. This is achieved via double silyl protection of the 11 beta, 17 alpha-diol, followed by selective desilylation of the 17 alpha-OH under basic conditions without the need for a fluoride source.