Discovery and Characterization of RGH-122, a Potent, Selective, and Orally Bioavailable V1a Receptor Antagonist.

The V1a receptor is a major contributor in mediating the social and emotional effects of arginine-vasopressin (AVP); therefore it represents a promising target in the treatment of several neuropsychiatric conditions. The aim of this research was to design and synthesize novel and selective V1a antagonists with improved in vitro and in vivo profiles. Through optimization and detailed SAR studies, we developed low nanomolar antagonists, and further characterizations led to the discovery of the clinical candidate compound 43 (RGH-122). The CNS activity of the compound was determined in a 3-chamber social preference test of autism in which RGH-122 successfully enhanced social preference with the lowest effective dose of 1.5 mg/kg.

Identification of Triazolopyridines as Selective α5-GABAA Receptor Negative Allosteric Modulators by a Hybridization Approach.

The identification and characterization of novel triazolopyridine derivatives with selective α5 subunit-containing GABAA receptor negative allosteric modulator (NAM) activity are disclosed. As a result of in silico screening of our corporate compound deck, we identified a moderately potent hit that was converted to an advanced hit bearing better physicochemical and pharmacological properties using a hybridization approach. Subsequent optimization led to the identification of in vitro potent and subtype-selective α5-GABAA receptor NAMs representing a new chemotype in this area.

Synthesis and Characterization of New V1A Antagonist Compounds: The Separation of Four Atropisomeric Stereoisomers.

A new class of selective vasopressin receptor 1A (V1A) antagonists was identified, where "methyl-scan" was performed around the benzene ring of the 5-hydroxy-triazolobenzazepine core. This led to the synthesis of two 10-methyl derivatives, each possessing a chiral axis and a stereogenic center. The four atropisomeric stereoisomers (involving two enantiomer pairs and atropisomeric diastereomers) could be successfully isolated and spectroscopically characterized. According to the in vitro pharmacological profiles of the compounds, the human V1A receptor has a strong preference toward the isomers having an aR axial chirality, the most active isomer being the aR,5S isomer. Furthermore, the structure-activity relationships obtained for the isomers and for the newly synthesized analogues could be tentatively explained by an in silico study.

Structure of the major degradant of ezetimibe.

In a recent contribution to this Journal Gajjar and Shah described the isolation and structure elucidation of the major alkaline degradant of ezetimibe, a lipid lowering agent [A.K. Gajjar, V.D. Shah, J. Pharm. Biomed. Anal. 55 (2011) 225-229]. Based on (1)H NMR, (13)C NMR and mass spectrometric studies the authors concluded that the structure of the degradant is 5-(4-fluorophenyl)-2-[(4-fluorophenylamino)-(4-hydroxyphenyl) methyl]-pent-4-enoic acid. In a subsequent "Letter to the Editor" submitted to the Journal, Barhate and Mohanra pointed out that the aforementioned structure is inconsistent with the spectroscopic data reported by Gajjar and Shah, consequently it must be wrong [Ch.R. Barhate, K. Mohanra, J. Pharm. Biomed. Anal. 55 (2011) 1237-1238]. However, Barhate and Mohanra did not offer a correct structure in their critical letter. Based on the cited NMR data we realised that previously we had had the same degradant in hand and had unambiguously determined its structure from detailed (1)H, (13)C, COSY, H-C HSQC, H-C HMBC and 1D-NOESY NMR investigations. Herein we report the correct structure to be (2R,3R,6S)-N,6-bis(4-fluorophenyl)-2-(4-hydroxyphenyl)-3,4,5,6-tetrahydro-2H-pyran-3-carboxamide. However, the structure is not new and was described earlier [G.Y.S.K. Swamy et al., Acta Cryst. E 61 (2005) o3608-o3610; K. Filip et al., J. Mol. Struct. 991 (2011) 162-170]. The aim of our present communication is to bring together the various threads of analytical effort involving this degradant into a compact and hopefully instructive conclusion on the pages of this Journal. For the sake of completeness and clarity we also list the correct NMR spectral assignments for ezetimibe which was also given partly erroneously in the earlier literature, and we propose a mechanism for the formation of the degradant.

Chemical and biological investigation of cyclopropyl containing diaryl-pyrazole-3-carboxamides as novel and potent cannabinoid type 1 receptor antagonists.

Obesity is a major clinical problem in the western world, and many molecular targets have been explored in the search for effective therapeutic agents. One of these, antagonism of the cannabinoid 1 (CB1) receptor, rose to prominence following reports demonstrating the positive modulation of food intake by the CB1 antagonist, rimonabant (3) (SR141716A). In the present study, various diaryl-pyrazole derivatives containing cycloalkyl building blocks were synthesized and tested for CB1 receptor binding affinities. Thorough structure-activity relationship (SAR) studies to optimize the pyrazole substituents led to several novel CB1 antagonists with K(i)

Hit-to-lead optimization of pyrrolo[1,2-a]quinoxalines as novel cannabinoid type 1 receptor antagonists.

Hit-to-lead optimization of a novel series of N-alkyl-N-[2-oxo-2-(4-aryl-4H-pyrrolo[1,2-a]quinoxaline-5-yl)-ethyl]-carboxylic acid amides, derived from a high throughput screening (HTS) hit, are described. Subsequent optimization led to identification of in vitro potent cannabinoid 1 receptor (CB1R) antagonists representing a new class of compounds in this area.

Nitrone derivatives of trolox as neuroprotective agents.

Synthesis of nitrone derivatives of trolox is described. Their biological evaluation was performed in vitro for scavenging different free radicals, inhibiting Fe(2+)-induced lipid peroxidation, and in vivo in a permanent middle cerebral artery occlusion model in mice. New compounds exert pharmacological activities comparable to or better than those of trolox or nitrone-type reference compounds.