Austin John Reeve

L‐694,247: a potent 5‐HT1D receptor agonist

1 The 5‐hydroxytryptamine (5‐HT) receptor binding selectivity profile of a novel, potent 5‐HT1D receptor agonist, L‐694,247 (2‐[5‐[3‐(4‐methylsulphonylamino)benzyl‐1,2,4‐oxadiazol‐5‐yl]‐1H‐indole‐3‐yl]ethylamine) was assessed and compared with that of the 5‐HT1‐like receptor agonist, sumatriptan. 2 L‐694,247 had an affinity (pIC50) of 10.03 at the 5‐HT1D binding site and 9.08 at the 5‐HT1B binding site (sumatriptan: pIC50 values 8.22 and 5.94 respectively). L‐694,247 retained good selectivity with respect to the 5‐HT1A binding site (pIC50 = 8.64), the 5‐HT1C binding site (6.42), the 5‐HT2 binding site (6.50) and the 5‐HT1E binding site (5.66). The pIC50 values for sumatriptan at these radioligand binding sites were 6.14, 5.0, < 5.0 and 5.64 respectively. Both L‐694,247 and sumatriptan were essentially inactive at the 5‐HT3 recognition site. 3 L‐694,247, like sumatriptan, displayed a similar efficacy to 5‐HT in inhibiting forskolin‐stimulated adenylyl cyclase in guinea‐pig substantia nigra although L‐694,247 (pEC50 = 9.1) was more potent than sumatriptan (6.2) in this 5‐HT1D receptor mediated functional response. L‐694,247 (pEC50 = 9.4) was also more potent than sumatriptan (6.5) in a second 5‐HT1D receptor mediated functional response, the inhibition of K+‐evoked [3H]‐5‐HT release from guinea‐pig frontal cortex slices. 4 The excellent agreement observed for L‐694,247 between the 5‐HT1D radioligand binding affinity and the functional potency confirm that the two functional models (the inhibition of forskolin‐stimulated adenylyl cyclase in guinea‐pig substantia nigra and the inhibition of K+‐evoked [3H]‐5‐HT release from guinea‐pig frontal cortex) do indeed reflect 5‐HT1D‐mediated events. 5 L‐694,247 is a novel, highly potent 5‐HT1D/5‐HT1B receptor ligand which should prove useful for the exploration of the physiological role of these receptors in animals.

Identification of C-2 Hydroxyethyl Imidazopyrrolopyridines as Potent JAK1 Inhibitors with Favorable Physicochemical Properties and High Selectivity over JAK2.

Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.

The chemical evolution of N,N-dimethyl-2-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]ethylamine (L-741,604) and analogues: Potent and selective agonists for 5-HT1D receptors☆

Optimisation of a series of 5-(heterocyclyl)tryptamines led to the identification of the symmetrically substituted, N-4 linked 1,2,4-triazole as the best indole C-5 substituent for 5-HT1D receptor affinity and selectivity. The triazole (8) is the most potent and selective, orally bioavailable, 5-HT1D receptor agonist identified to date, showing an order of magnitude greater potency than the clinical compound sumatriptan with improved subtype selectivity.

Synthesis of azabicyclic pyrazine derivatives as muscarinic agonists and the preparation of a chloropyrazine analogue with functional selectivity at sub-types of the muscarinic receptor

The synthesis of quinuclidine and azanorbornyl pyrazine derivatives has yielded highly potent and efficacious muscarinic agonists; chloro-substitution in the pyrazine ring of the quinuclidine analogue resulted in the formation of a derivative with both enantiomers displaying partial agonist character but, more importantly, functional selectivity at the M1, M2 and M3 sub-types of the muscarinic receptor.