Dennis V. Nazareno

Piperazine-based CCR5 antagonists as HIV-1 inhibitors. I: 2(S)-methyl piperazine as a key pharmacophore element.

Optimization of the piperidino-piperazines 1 and 2 provided early leads 3 and 4, which showed good activity in the CCR5-RANTES binding assay and in antiviral assays. A systematic study around these structures showed that the 2(S)-methyl piperazine is essential for CCR5 affinity, which is further enhanced by forming the 2,6-dimethyl benzamide of the piperidine.

Synthesis and chemistry of thia-analogs of the anti-mitotic podophyllium lignans

Abstract The Michael-aldol product (8) from PhSH-PhCHO-2(5H)-furanone is converted by acids to the tricyclic compound (9), without the intermediacy of the olefin (10). The podophyllotoxin analog (22) was similarly obtained. The all-trans compounds were isomerised by DBU to the cis lactones. Hydroxylated analogs (26) and (33) were produced by reacting 2-(5H)-furanone with appropriate 2-mercaptobenzophenones. Thermal rearrangement of the sulfoxide (35) initially gave the spirocyclic isomer (37), then formed dimeric products on prolonged heating.

Synthesis and anti-herpes activity of some a-ring functionalized dehydroabietane derivatives

Abstract Dehydroabietic acid 5 was converted to the exocyclic olefin 7 by applying the Barton decarboxylation protocol. The latter served as key intermediate for the stereoselective synthesis of a variety of ring-A functionalized derivatives. Compounds 13 and 16 turned out to be active against the herpes virus (HSV-2) in the standard plaque assay and seem to interfere with an early event in viral replication.

Metabolic stabilization of benzylidene ketal M2 muscarinic receptor antagonists via halonaphthoic acid substitution

The potential toxicological liabilities of the M(2) muscarinic antagonist 1 were addressed by replacing the methylenedioxyphenyl moiety with a p-methoxyphenyl group, resulting in M(2) selective compounds such as 3. Several halogenated naphthamide derivatives of 3 were studied in order to improve the pharmacokinetic profile via blockage of oxidative metabolism. Compound 4 demonstrated excellent M(2) affinity and selectivity, human microsomal stability, and oral bioavailability in rodents and primates.

Synthesis and structure–Activity relationships of M2-Selective muscarinic receptor ligands in the 1-[4-(4-Arylsulfonyl)-phenylmethyl]-4-(4-piperidinyl)-piperazine family

The synthesis and muscarinic binding properties of compounds based on the 1-[4-(4-arylsulfonyl)phenylmethyl]-4-(1-aroyl-4-piperidinyl)-piperazine skeleton are described. For compounds, substituted with appropriately configured methyl groups at the benzylic center and at the piperazine 2-position, high levels of selective, M(2) subtype affinity could be obtained, particularly when the terminal N-aroyl residue was ortho-substituted.

Synthetic inhibitors of interleukin-6 I: 2,3,7,8-tetrahydro-4-aryl-1H-cyclopent [e] imidazo [1,2-a]- pyridin-5(6H)-one and related compounds

A versatile synthetic route to the title class of compounds and the development of an orally absorbed analogue of the lead structure are described. The minimum structural requirements needed in the compounds related to 1 for the inhibition of interleukin-6 were identified.