Discovery of Potent, Selective, and Peripherally Restricted Pan-Trk Kinase Inhibitors for the Treatment of Pain.

Hormones of the neurotrophin family, nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), are known to activate the family of Tropomyosin receptor kinases (TrkA, TrkB, and TrkC). Moreover, inhibition of the TrkA kinase pathway in pain has been clinically validated by the NGF antibody tanezumab, leading to significant interest in the development of small molecule inhibitors of TrkA. Furthermore, Trk inhibitors having an acceptable safety profile will require minimal brain availability.

Discovery of Allosteric, Potent, Subtype Selective, and Peripherally Restricted TrkA Kinase Inhibitors.

Tropomyosin receptor kinases (TrkA, TrkB, TrkC) are activated by hormones of the neurotrophin family: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4). Moreover, the NGF antibody tanezumab has provided clinical proof of concept for inhibition of the TrkA kinase pathway in pain leading to significant interest in the development of small molecule inhibitors of TrkA. However, achieving TrkA subtype selectivity over TrkB and TrkC via a Type I and Type II inhibitor binding mode has proven challenging and Type III or Type IV allosteric inhibitors may present a more promising selectivity design approach.

Highly potent and selective Na1.7 inhibitors for use as intravenous agents and chemical probes.

The discovery and selection of a highly potent and selective Na1.7 inhibitor PF-06456384, designed specifically for intravenous infusion, is disclosed. Extensive in vitro pharmacology and ADME profiling followed by in vivo preclinical PK and efficacy model data are discussed.

One-Pot Synthesis of α-Branched N-Acylamines via Titanium-Mediated Condensation of Amides, Aldehydes, and Organometallics.

A three-component, titanium-mediated synthesis of α-branched N-acylamines from commercial or readily accessible amides, aldehydes, and organometallic reagents is reported. The transformation proceeds under mild reaction conditions and tolerates a variety of functional groups (including nitrile, carbamate, olefin, basic amine, furan, and other sensitive heteroaromatics) to generate a large umbrella of α-branched N-acylamine products in high yields. The operationally practical procedure enables the use of this method in parallel chemical synthesis, a valuable feature that can facilitate the screening of bioactive molecules by medicinal chemists.

Multiparameter optimization in CNS drug discovery: design of pyrimido[4,5-d]azepines as potent 5-hydroxytryptamine 2C (5-HT₂C) receptor agonists with exquisite functional selectivity over 5-HT₂A and 5-HT₂B receptors.

A series of 4-substituted pyrimido[4,5-d]azepines that are potent, selective 5-HT2C receptor partial agonists is described. A rational medicinal chemistry design strategy to deliver CNS penetration coupled with SAR-based optimization of selectivity and agonist potency provided compounds with the desired balance of preclinical properties. Lead compounds 17 (PF-4479745) and 18 (PF-4522654) displayed robust pharmacology in a preclinical canine model of stress urinary incontinence (SUI) and no measurable functional agonism at the key selectivity targets 5-HT2A and 5-HT2B in relevant tissue-based assay systems.

Chiral anthracene and anthrone templates as stereocontrolling elements in Diels-Alder/retro Diels-Alder sequences.

The development of chiral anthracene templates for use in Diels-Alder/retro Diels-Alder sequences is described. A summary of past results and new progress is reported.