Michael S. Hadley

1,3-Biarylureas as Selective Non-peptide Antagonists of the Orexin-1 Receptor

This communication reports SARs for the first orexin-1 receptor antagonist series of 1-aryl-3-quinolin-4-yl and 1-aryl-3-naphthyridin-4-yl ureas. One of these compounds, 31 (SB-334867), has excellent selectivity for the orexin-1 receptor, blood-brain barrier permeability and shows in vivo activity following ip dosing.

Identification of (-)-cis-6-acetyl-4S-(3-chloro-4-fluoro-benzoylamino)- 3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3S-ol as a potential antimigraine agent.

Optimisation of novel cis- and trans-4-(substituted-amido)benzopyran-3-ol derivatives has led to the identification of SB-220453 20 with an in vivo pre-clinical CNS profile predictive of potential antimigraine activity.

N-(substituted-phenyl) piperazines: antagonists with high binding and functional selectivity for dopamine D4 receptors

Abstract A series of N-(substituted-phenyl) piperazine derivatives was prepared as selective antagonists of the dopamine D 4 receptor. Many analogues possessed a binding selectivity of over 100 fold for D 4 over D 2 receptors. In functional studies in the microphysiometer, compound 24 showed a selectivity over dopamine D 2 receptors of greater than 1000 fold.

Heterocyclic analogues of 2-aminotetralins with high affinity and selectivity for the dopamine D3 receptor

A novel series of 5,6,7,8-tetrahydroquinazolines, 4,5,6,7-tetrahydroindazoles and 4,5,6,7-tetrahydrobenzothiazoles has been prepared, having high affinity and selectivity for the dopamine D3 receptor. The 4-methoxy-5,6,7,8-tetrahydroquinazoline 6i and 2-amino-4,5,6,7-tetrahydrobenzothiazole 8 proved to be agonists with among the highest D3 receptor affinities and selectivities reported to date.

Benzopyran potassium channel activators related to cromakalim - heterocyclic amide replacements at position 4.

Abstract The synthesis and antihypertensive activity in spontaneously hypertensive rats (SHR) of a series of benzopyran potassium channel activators related to cromakalin (1) where the pyrrolidinone at position 4 is replaced by a number of potential heterocyclic amide and ester bioisosteres is reported. Aminotriazole 6 was shown to be the most potent amide replacement in this series.

Novel 2,3,4,5-tetrahydro-1H-3-benzazepines with high affinity and selectivity for the dopamine D3 receptor.

Starting from the dopamine D3 receptor antagonist SB-277011 1, a series of 2,3,4,5-tetrahydro-1H-3-benzazepines has been identified with high affinity for the dopamine D3 receptor and selectivity over the D2 receptor. The 3-acetamido-2-fluorocinnamide derivative 20 gave high D3 receptor affinity (pKi 8.4) with 130-fold selectivity over the 2, receptor.

A novel series of 2-aminotetralins with high affinity and selectivity for the dopamine D3 receptor

Abstract A novel series of N-[4-(4-Phenylbenzoylamino)butyl]-1,2,3,4-tetrahydro-2-naphthylamines with high affinity and selectivity for the dopamine D3 receptor has been prepared. The 5-cyclopropylmethyloxy 3j, methanesulfonyloxy 3k and trifluoromethanesulfonyloxy 3l derivatives represent some of the highest affinity (pKis 8.6–8.9) and most selective (200–320-fold) dopamine D3 receptor antagonists reported to date.

The synthesis, reduction and cyclisation of N-(3-butynyl)- morpholin-and-thiomorpholin-2,6-diones

Abstract A nove one-step synthesis of N-(3-butenyl) imides (1) from dicarboxylic acids, and the sodium borohydride reduction/formic acid cyclisation of the N-(3-butenyl)-morpholin- and thiomorpholin-2,6-diones are described.

Novel 1,2,3,4-tetrahydroisoquinolines with high affinity and selectivity for the dopamine D3 receptor.

Using clearance and brain penetration studies as a screen, tetrahydroisoquinoline 3 was identified as a lead having low clearance in rats (CLb 20 ml/min/kg). Introduction of a 7-CF3SO2O- substituent into the tetrahydroisoquinoline, followed by replacement of the biphenylamido group of 3 by a 3-indolylpropenamido group gave 31, having high D3 receptor affinity (pKi 8.4) and 150 fold selectivity over the D2 receptor.

Stereochemical differentiation of anticonvulsant and antihypertensive effects in 4-(fluorobenzoylamino)-benzopyrans

Abstract Replacement of the 2-pyrrolidinone group of cromakalim 1 by the fluorobenzoylamino group has introduced anticonvulsant activity. It is particularly noteworthy that this activity is found predominantly in the 3R,4S enantiomeric series. In contrast, antihypertensive activity is restricted to the 3S,4R enantiomeric series.