Growing evidence suggests that drug and alcohol use are fueling the heterosexual transmission of HIV among African Americans. This study aims to examine the relative contribution of drug and alcohol ...use of male and female partners to risks of heterosexual transmission of HIV among 535 African American HIV serodiscordant couples (
N
= 1,070 participants) who participated in an HIV prevention trial. Associations found between use of drugs and alcohol by one or both partners and sexual risk indicators varied by type of substance and whether male or female partner or both partners reported use. The findings suggest multiple ways in which substance use of male and female partners may be contributing to the heterosexual transmission of HIV and other STDs among African Americans and underscore the need for HIV prevention strategies to address dyadic patterns of substance use that lead to sexual risks.
Previously reported studies from these laboratories described the design of a novel series of high-affinity NK1 antagonists based on the 4,4-disubstituted piperidine ring system. Further ...structure-activity studies have now established that for high NK1 affinity the benzyl ether side chain must be 3,5-disubstituted and highly lipophilic, the optimal side chain being the 3, 5-bis(trifluoromethyl)benzyl ether, 12 (hNK1 IC50 = 0.95 nM). Additional studies have shown that this class of NK1 antagonist tolerates a wider range of substituents on the piperidine nitrogen, including acyl (38) (hNK1 IC50 = 5.3 nM) and sulfonyl (39) (hNK1 IC50 = 5.7 nM) derivatives. Following preliminary pharmacokinetic analysis, two compounds (32 and 43) were selected for in vivo study in the resiniferotoxin-induced vascular leakage model, both showing excellent profiles (ID50 = 0.22 and 0.28 mg/kg, respectively).
The synthesis of both
cis- and
trans-crobarbatic acid is reported. The five-step sequence proceeds in high yield and with control of both relative and absolute stereochemistry. The key step in the ...synthesis is the Birch reductive alkylation of a chiral furoic acid which sets the absolute stereochemistry of the products. The stereochemistry of the compounds described was proven unambiguously by X-ray crystallography on one synthetic intermediate and on
trans-crobarbatic acid.
The preparation and Birch reduction of chiral 3-methyl-2-furoic acid derivatives is described. Using a C
2 symmetrical amine as a chiral auxiliary, very high levels of sterochemical control could be ...obtained. Moreover, the auxiliary could be removed conveniently by heating in 6M HCl to liberate a carboxylic acid of high enantiomeric purity. The relative stereochemistry of the Birch reduced amides (and therefore the absolute stereochemistry of the corresponding acids) was determined unambiguously from an X-ray crystal structure.
The stereoselective Birch reduction of 3-methyl-2-furoic acid derivatives is described.
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