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Roffey J.R.A.,University College London | Ott G.R.,Discovery and Product Development
Annual Reports in Medicinal Chemistry | Year: 2014

The atypical protein kinase C (PKC) isoforms (zeta and iota) have recently garnered attention as therapeutic targets for oncology, metabolic diseases as well as other indications. Though the novel and classical PKC isoforms have been interrogated as therapeutic intervention points and inhibitors of these isoforms (both selective and nonselective) have advanced to the clinic, no atypical inhibitor has been validated at this level. Recent biological studies have demonstrated the direct role for atypical PKC isoforms in specific cancers and the preclinical validity of atypical PKCs as therapeutic intervention points. This review will cover the structure/function of atypical PKCs versus novel and classical PKC isoforms, the implications in disease states, focusing on oncology, and a summary of both non-ATP competitive and ATP-competitive atypical PKC inhibitors. © 2014 Elsevier Inc.

Hudkins R.L.,Discovery and Product Development | Josef K.A.,Discovery and Product Development | Becknell N.C.,Discovery and Product Development | Aimone L.D.,Discovery and Product Development | And 4 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2014

A series of fused cyclopropyl-4,5-dihydropyridazin-3-one (3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one) phenoxypiperidine analogs was designed and synthesized, leading to the identification of (1R,6S)-5-[4-(1-cyclobutyl- piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (R,S-4a) as a second-generation pyridazin-3-one H3R antagonist. Compound R,S-4a was a potent H3R functional antagonist in vivo in the rat dipsogenia model, demonstrated potent wake activity in the rat EEG/EMG model, and enhanced short-term memory in the rat social recognition memory model at doses as low as 0.03-0.3 mg/kg po. © 2014 Elsevier Ltd. All rights reserved.

Hudkins R.L.,Discovery and Product Development | Becknell N.C.,Discovery and Product Development | Lyons J.A.,Discovery and Product Development | Aimone L.D.,Discovery and Product Development | And 5 more authors.
European Journal of Medicinal Chemistry | Year: 2015

A novel series of 3,4-diaza-bicyclo[4.1.0]hept-4-en-2-ones were designed and synthesized as H3R analogs of irdabisant 6. Separation of the isomers, assignment of the stereochemistry by crystallography, and detailed profiling of diastereomers 25 and 26 led to the identification of (1R,6S)-5-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)propoxy]phenyl}-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one 25 as a potential second generation H3R candidate. Diastereomer 25 had high H3R binding affinity, excellent selectivity, displayed potent H3R functional antagonism and robust wake-promoting activity in vivo, and showed acceptable pharmacokinetic and pharmaceutical profiles for potential further development. © 2015 Elsevier Masson SAS.

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