The discovery and preclinical evaluation of BMS-707035, a potent HIV-1 integrase strand transfer inhibitor.

BMS-707035 is an HIV-1 integrase strand transfer inhibitor (INSTI) discovered by systematic optimization of N-methylpyrimidinone carboxamides guided by structure-activity relationships (SARs) and the single crystal X-ray structure of compound 10. It was rationalized that the unexpectedly advantageous profiles of N-methylpyrimidinone carboxamides with a saturated C2-substitutent may be due, in part, to the geometric relationship between the C2-substituent and the pyrimidinone core. The single crystal X-ray structure of 10 provided support for this reasoning and guided the design of a spirocyclic series 12 which led to discovery of the morpholino-fused pyrimidinone series 13. Several carboxamides derived from this bicyclic scaffold displayed improved antiviral activity and pharmacokinetic profiles when compared with corresponding spirocyclic analogs. Based on the excellent antiviral activity, preclinical profiles and acceptable in vitro and in vivo toxicity profiles, 13a (BMS-707035) was selected for advancement into phase I clinical trials.

In vitro antiviral characteristics of HIV-1 attachment inhibitor BMS-626529, the active component of the prodrug BMS-663068.

BMS-663068 is the phosphonooxymethyl prodrug of BMS-626529, a novel small-molecule attachment inhibitor that targets HIV-1 gp120 and prevents its binding to CD4(+) T cells. The activity of BMS-626529 is virus dependent, due to heterogeneity within gp120. In order to better understand the anti-HIV-1 spectrum of BMS-626529 against HIV-1, in vitro activities against a wide variety of laboratory strains and clinical isolates were determined. BMS-626529 had half-maximal effective concentration (EC(50)) values of <10 nM against the vast majority of viral isolates; however, susceptibility varied by >6 log(10), with half-maximal effective concentration values in the low pM range against the most susceptible viruses. The in vitro antiviral activity of BMS-626529 was generally not associated with either tropism or subtype, with few exceptions. Measurement of the binding affinity of BMS-626529 for purified gp120 suggests that a contributory factor to its inhibitory potency may be a relatively long dissociative half-life. Finally, in two-drug combination studies, BMS-626529 demonstrated additive or synergistic interactions with antiretroviral drugs of different mechanistic classes. These results suggest that BMS-626529 should be active against the majority of HIV-1 viruses and support the continued clinical development of the compound.

Synthesis and antibacterial activity of nocathiacin I analogues.

Stereoselective reduction of dehydroalanine double bond in nocathiacin I afforded the primary amide 2. Enzymatic hydrolysis of the amide 2 provided the carboxylic acid 3, which upon coupling with a variety of amines furnished amides 4-32. Some of these semi-synthetic derivatives have retained very good antibacterial activity and have improved aqueous solubility.

Novel semi-synthetic nocathiacin antibiotics: synthesis and antibacterial activity of bis- and mono-O-alkylated derivatives.

Several semi-synthetic bis- and mono-O-alkyl nocathiacin derivatives were synthesized and evaluated for antibacterial activity. Mono-O-alkyl N-hydroxyindole analogues 3a-l were prepared by regioselective alkylation. Bis-O-alkyl nocathiacins 4a-f were obtained by treatment with base and excess electrophile. A one-pot protection-alkylation-deprotection strategy was developed for the preparation of mono-O-alkyl hydroxypyridine analogues 5a,b. Most of the bis- and mono-O-alkyl nocathiacins maintained good in vitro activity but showed reduced in vivo efficacy when compared with the natural product. The excellent in vivo activity and improved water solubility of phosphate analogues 3m and 4g suggest their use as potential pro-drugs.

Nocathiacin I analogues: synthesis, in vitro and in vivo biological activity of novel semi-synthetic thiazolyl peptide antibiotics.

Several nocathiacin I analogues (4-35) were synthesized and evaluated for their antibacterial activity. Most of these semi-synthetic analogues retained very good in vitro and in vivo antibacterial activity of 1.

Phosphonooxymethyl prodrugs of the broad spectrum antifungal azole, ravuconazole: synthesis and biological properties.

Synthesis of phosphonooxymethyl derivatives of ravuconazole, 2 (BMS-379224) and 3 (BMS-315801) and their biological evaluation as potential water-soluble prodrugs of ravuconazole are described. The phosphonooxymethyl ether analogue 2 (BMS-379224) and N-phosphonooxymethyl triazolium salt 3 (BMS-315801) were both prepared from ravuconazole (1) and bis-tert-butyl chloromethylphosphate, but under two different conditions. Both derivatives were highly soluble in water and converted to the parent in alkaline phosphatase, and also in vivo (rat). However, BMS-315801 was found to be less stable than BMS-379224 in water at neutral pH. BMS-379224 (2) has proved to be one of the most promising prodrugs of ravuconazole that we tested, and it is currently in clinical evaluation as an intravenous formulation of the broad spectrum antifungal azole, ravuconazole.