Susan R. Jenkins

Discovery of BMS-955176, a Second Generation HIV-1 Maturation Inhibitor with Broad Spectrum Antiviral Activity

HIV-1 maturation inhibition (MI) has been clinically validated as an approach to the control of HIV-1 infection. However, identifying an MI with both broad polymorphic spectrum coverage and good oral exposure has been challenging. Herein, we describe the design, synthesis, and preclinical characterization of a potent, orally active, second generation HIV-1 MI, BMS-955176 (2), which is currently in Phase IIb clinical trials as part of a combination antiretroviral regimen.

Synthesis of 9-(3-deoxy-3-C-methyl-β-d-xylofuranosyl)-adenine: a branched-chain sugar analog of cordycepin

Abstract Reaction of methyl 2,3-anhydro-5- O -trityl-β- d -ribofuranoside ( 4 ) with methyl-magnesium chloride gave a mixture of methyl 3-chloro-3-deoxy-5- O -trityl-β- d -xylofuranoside ( 5 ) and methyl 3-deoxy-3- C -methyl-5- O -trityl-α- d -xylofuranoside ( 6 ). Removal of the trityl group from 6 gave methyl 3-deoxy-3- C -methyl-β- d -xylofuranoside ( 9 ), which, on treatment with p -nitrobenzoyl chloride, gave methyl 3-deoxy-3- C -methyl-2,5-di- O -( p -nitrobenzoyl)-β- d -xylofuranoside ( 10 ). The glycosyl chloride ( 15 ) derived from 10 reacted with 6-(benzamido)chloromercuripurine to give 6-(benzamido)-9-[3-deoxy-3- C -methyl-2,5-di- O -( p -nitrobenzoyl)- d -xylofuranosyl]purine ( 16 ). Alkaline methanolysis of 16 produced 9-(3-deoxy-3- C -methyl-α- d -xylofuranosyl)-adenine (α- 1 ) and 9-(3-deoxy-3- C -methyl-β- d -xylofuranosyl)adenine (β- 1 ) in the ratio of 1:4. Treatment of 6 with benzoyl chloride gave methyl 2- O -benzoyl-3-deoxy-3- C -methyl-5- O -trityl-β- d -xylofuranoside ( 17 ). The trityl group was removed from 17 to give methyl 2- O -benzoyl-3-deoxy-3- C -methyl-β- d -xylofuranoside ( 18 ), which was converted into methyl 2,5-di- O -benzoyl-3-deoxy-3- C -methyl-β- d -xylofuranoside ( 19 ). When the glycosyl halide ( 20 ) obtained from 19 reacted with 6-(benzamido)chloromercuripurine, 6-(benzamido)-9-(2,5-di- O -benzoyl-3-deoxy-3- C -methyl- d -xylofuranosyl)-purine ( 21 ) was produced. Ammonolysis of 21 gave α- 1 and β- 1 in the ratio of 1:16.

Inhibitors of human immunodeficiency virus type 1 (HIV-1) attachment 13. Synthesis and profiling of a novel amminium prodrug of the HIV-1 attachment inhibitor BMS-585248.

In vitro studies suggested that the ammonium salt 2 could be a viable prodrug of the HIV-1 attachment inhibitor 1. Increased systemic exposure of the parent drug 1 following oral administration of the amminium salt 2 when compared to similar studies using solution dosing of the parent compound was observed in the in vivo studies in both rats and dogs. At high doses, the improvement in oral exposure of the parent drug was even more evident, indicating that the increased solubility of the amminium salt 2 can overcome dissolution-limited absorption and demonstrating the potential utility of this compound as a prodrug of 1.

The Design, Synthesis and Structure-Activity Relationships Associated with C28 Amine-Based Betulinic Acid Derivatives as Inhibitors of HIV-1 Maturation

The design and synthesis of a series of C28 amine-based betulinic acid derivatives as HIV-1 maturation inhibitors is described. This series represents a continuation of efforts following on from previous studies of C-3 benzoic acid-substituted betulinic acid derivatives as HIV-1 maturation inhibitors (MIs) that were explored in the context of C-28 amide substituents. Compared to the C-28 amide series, the C-28 amine derivatives exhibited further improvements in HIV-1 inhibitory activity toward polymorphisms in the Gag polyprotein as well as improved activity in the presence of human serum. However, plasma exposure of basic amines following oral administration to rats was generally low, leading to a focus on moderating the basicity of the amine moiety distal from the triterpene core. The thiomorpholine dioxide (TMD) 20 emerged from this study as a compound with the optimal antiviral activity and an acceptable pharmacokinetic profile in the C-28 amine series. Compared to the C-28 amide 3, 20 offers a 2- to 4-fold improvement in potency towards the screening viruses, exhibits low shifts in the EC50 values toward the V370A and ΔV370 viruses in the presence of human serum or human serum albumin, and demonstrates improved potency towards the polymorphic T371A and V362I virus variants.