4-(Phenylsulfonyl)piperidines:  Novel, Selective, and Bioavailable 5-HT_2AReceptor Antagonists

Abstract

On the basis of a spirocyclic ether screening lead, a series of acyclic sulfones have been identified as high-affinity, selective 5-HT(2A) receptor antagonists. Bioavailability lacking in the parent, 1-(2-(2,4-difluorophenyl)ethyl)-4-(phenylsulfonyl)piperidine (12), was introduced by using stability toward rat liver microsomes as a predictor of bioavailability. By this means, the 4-cyano- and 4-carboxamidophenylsulfonyl derivatives 26 and 31 were identified as orally bioavailable, brain-penetrant analogues suitable for evaluation in animal models. Bioavailability was also attainable by N substitution leading to the N-phenacyl derivative 35. IKr activity detected through counterscreening was reduced to insignificant levels in vivo with the latter compound.

Selective Nucleoside Triphosphate Diphosphohydrolase-2 (NTPDase2) Inhibitors: Nucleotide Mimetics Derived from Uridine-5′-carboxamide

“…Simulated gastric acid was prepared as previously described: 53,54 pepsin (3.20 g), NaCl (2.0 g), and HCl (1 M, 80 mL) were mixed with distilled water to obtain 1000 mL, and the resulting solution was stored at 4 °C. Rat liver microsomes were prepared as described with slight modifications: 53,55,61 fresh rat liver (6.5 g) was homogenized in 30 mL of freshly prepared Dulbecco's phosphate buffered saline (DPBS) consisting of 132. …”

Synthesis and biological evaluation of (phenylpiperazinyl-propyl)arylsulfonamides as selective 5-HT2A receptor antagonists

“…MDL-100907 (3) which is one of the more highly studied selective 5-HT 2A antagonists is an arylpiperidine, 6,7 and fananserin (4) is a newer arylpiperazine antagonist. 8 Piperazine amides and sulfonamides, such as EMD-281014 (5) 9 and 6, show high affinity as 5-HT 2A antagonists. [10][11][12] Several pharmacophore models for 5-HT 2A receptors have been proposed based on the structure-activity relationships of known antagonists.…”

Synthesis and antimicrobial activity of 1-benzhydryl-sulfonyl-4-(3-(piperidin-4-yl) propyl)piperidine derivatives against pathogens of Lycopersicon esculentum: A structure-activity evaluation study

“…The piperidine scaffold as wide-ranging in its therapeutic uses as it is ubiquitously found in drugs. It is a key structural component of successful antiParkinson's drugs (Klockgether et al, 1996) and displays antipsychotic (Fletcher et al, 2002), antiviral (Christopher et al, 2001), metabolic (Lihu et al, 1998), antimicrobial (Ramalingan et al, 2003a(Ramalingan et al, , 2003b(Ramalingan et al, , 2004, antidepressants (Amat et al, 1996), acetylcholinesterase (Jean-Marie et al, 2001), antimalarial (Maniyan et al, 2006), and anticonvulsant activity (Reddy et al, 1997;Matthew et al, 1998). In 1935, Domargk showed the therapeutic value of group of compounds known as sulfonamides.…”