Derivatives of chiro-inositol have been recently shown to mediate many important biological processes. This work addresses the question of whether phosphatidylinositol-specific phospholipase C (PI-PLC) could be involved in the generation of these chiro-inositol derivatives. Two diastereomers of the analog of phosphatidylinositol containing 1D- and 1L-chiro-inositol have been synthesized. 1D-2-O-(1,2-O-Dipalmitoyl-sn-glycero-3-phospho)-chiro-inositol (1D-chiro-PI) was synthesized in 12 steps starting from 1D-2,3,4,5-O-tetrakis(methoxymethylene)-myo-inositol by the inversion of the hydroxyl group at the 1-position of inositol followed by several protection/deprotection and phosphorylation steps. IL-2-O-(1,2-O-Dipalmitoyl-sn-glycero-3-phospho)-chiro-inositol (1L-chiro-PI) was synthesized in eight steps starting from 1L-chiro-inositol using regioselective silylation of the hydroxyl group at the 2-position of chiro-inositol in a key synthetic stage. Both diastereomers were subjected to cleavage by PI-PLC from Bacillus thuringiensis. The reaction of 1L-chiro-PI produced chiro-inositol 1,2-cyclic phosphate, however, at the rate of 10(-3) of that attained with the natural substrate, phosphatidylinositol. On the other hand, 1D-chiro-PI was found to be resistant to PI-PLC. These results suggest that the natural chiro-inositol derivatives should have the 1L-configuration if they are produced by PI-PLC, which is in contrast to the 1D-configuration reported by others. We therefore have isolated chiro-inositol from the total bovine liver lipid and determined its absolute configuration. The obtained chiro-inositol was found to be exclusively of the 1L-configuration, with the enantiomeric purity exceeding 99%.
The goal of this study was to identify a structurally distinct D(4)-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.
A new series of dopamine D4 receptor agonists, 1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes, was designed through the modification of known dopamine D4 receptor agonist PD 168077. Replacement of the amide group with a methylene-oxime moiety produced compounds with improved stability and efficacy. Structure-activity relationsips (SAR) of the aromatic ring linked to the N-4-piperazine ring confirmed the superiority of 2-pyridine as a core for D4 agonist activity. A two-methylene linker between the oxime group and the N-1-piperazine ring displayed the best profile. New dopamine D4 receptor agonists, exemplified by (E)-1-(4-chlorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-methyloxime (59a) and (E)-1-(3-chloro-4-fluorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-methyloxime (64a), exhibited favorable pharmacokinetic profiles and showed oral bioavailability in rat and dog. Subsequent evaluation of 59a in the rat penile erection model revealed in vivo activity, comparable in efficacy to apomorphine. Our results suggest that the oximes provide a novel structural linker for 4-arylpiperazine-based D4 agonists, possessing leadlike quality and with potential to develop a new class of potent and selective dopamine D4 receptor agonists.
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