Paul J. Gilligan

Effects of CRF1 receptor antagonists and benzodiazepines in the Morris water maze and delayed non-matching to position tests

RationaleBenzodiazepines continue to be widely used for the treatment of anxiety, but it is well known that benzodiazepines have undesirable side effects, including sedation, ataxia, cognitive deficits and the risk of addiction and abuse. CRF1 receptor antagonists are being developed as potential novel anxiolytics, but while CRF1 receptor antagonists seem to have a better side-effect profile than benzodiazepines with respect to sedation and ataxia, the effects of CRF1 receptor antagonists on cognitive function have not been well characterized. It is somewhat surprising that the potential cognitive effects of CRF1 receptor antagonists have not been more fully characterized since there is some evidence to suggest that these compounds may impair cognitive function.ObjectiveThe Morris water maze and the delayed non-matching to position test are sensitive tests of a range of cognitive functions, including spatial learning, attention and short-term memory, so the objective of the present experiments was to assess the effects of benzodiazepines and CRF1 receptor antagonists in these tests.ResultsThe benzodiazepines chlordiazepoxide and alprazolam disrupted performance in the Morris water maze and delayed non-matching to position at doses close to their therapeutic, anxiolytic doses. In contrast, the CRF1 receptor antagonists DMP-904 and DMP-696 produced little or no impairment in the Morris water maze or delayed non-matching to position test even at doses 10-fold higher than were necessary to produce anxiolytic effects.ConclusionsThe results of the present experiments suggest that, with respect to their effects on cognitive functions, CRF1 receptor antagonists seem to have a wider therapeutic index than benzodiazepines.

Imidazo[4,5-c]pyridines as corticotropin releasing factor receptor ligands

A series of high affinity CRF receptor ligands with an imidazo[4,5-c]pyridine core is described. Individual analogues were synthesized and tested in vitro in rat brain receptors to determine binding affinity. The best compound was further tested in the dog N-in-1 pharmacokinetic model to assess oral bioavailability at 1 mg/kg po.

CRF ligands via Suzuki and Negishi couplings of 3-pyridyl boronic acids or halides with 2-benzyloxy-4-chloro-3-nitropyridine.

A series of imidazo[4,5-b]pyridines with a 7-(3-pyridyl) substituent is described as high affinity CRF receptor ligands. Individual analogues were synthesized from key intermediates obtained via palladium-catalyzed coupling of 3-pyridyl zinc or boronic acid organometallic intermediates with 2-benzyloxy-4-chloro-3-nitropyridine 12.

Corticotropin-releasing factor receptor antagonists.

Corticotropin-releasing factor (CRF) coordinates the neural, endocrine and immune responses of the body to stress. Therefore, CRF receptors are important targets for the design of drugs for depression, anxiety and stress-related disorders. Several laboratories have published extensive preclinical and limited clinical research into the role of CRF in human disease. This review covers developments in the patent literature during 2002 – 2006 and outlines the prospects for CRF-based therapy for mental illness.

Novel phenylalanine derived diamides as Factor XIa inhibitors.

The synthesis, structural activity relationships (SAR), and selectivity profile of a potent series of phenylalanine diamide FXIa inhibitors will be discussed. Exploration of P1 prime and P2 prime groups led to the discovery of compounds with high FXIa affinity, good potency in our clotting assay (aPPT), and high selectivity against a panel of relevant serine proteases as exemplified by compound 21. Compound 21 demonstrated good in vivo efficacy (EC50=2.8μM) in the rabbit electrically induced carotid arterial thrombosis model (ECAT).

Synthesis of 6-Substituted Imidazo[4,5-d]pyridazin-7-ones

A novel synthesis of 6-substituted imidazo[4,5-d]pyridazin-7-ones is described, which employs 1,2-disubstituted 4-aroylimidazole-5-carboxylates as key intermediates.

Synthesis and structure-activity relationships of pyrido[3,2-b]pyrazin-3(4H)-ones and pteridin-7(8H)-ones as corticotropin-releasing factor-1 receptor antagonists.

Pyrido[3,2-b]pyrazin-3(4H)-ones and pteridin-7(8H)-ones were evaluated as corticotropin-releasing factor-1 receptor antagonists. The synthesis, SAR studies and pharmacokinetic evaluation of these analogs are described herein.