Ashok Bhandari

Studies on cyclodepsipeptides - part II : The total synthesis of jaspamide and geodiamolide-D

The total synthesis of cyclodepsipeptides jaspamide and geodiamolide D have been presented.

PTP1B inhibitors: Synthesis and evaluation of difluoro-methylenephosphonate bioisosteres on a sulfonamide scaffold

We have synthesized and evaluated a series of triaryl sulfonamide-based PTP1B inhibitors in which a difluoro-methylenephosphonate group of a potent lead has been replaced by potential bioisosteric replacements. Several mono- or di-charged compounds (8a, 8b, and 15a) were shown exhibit inhibitory activity in the low micromolar range, demonstrating the feasibility of using this approach in identifying non-phosphonate pTyr mimetics in a small molecular scaffold. These results also provide a useful indication of the relative effectiveness of these pTyr mimetics.

1β-methylthienamycin: some stereocontrolled approaches towards the key intermediate

Abstract Two stereocontrolled approaches towards a precursor of 1 β-methylthienamycin, have been accomplished by involving stereospecific hydrogenation of 13 and stereoselective hydroboration oxidation of 9. The latter compounds were obtained from the easily accessible chiral building block 7. The hydroboration-oxidation approach was extended to 18 in which the optically active 1R- (1-hydroxy ethyl) side-chain was incorporated. The highly stereoselective hydroboration-oxidation reaction of 9 is explained by considering Houks models.

Tu1869 Establishing the Human Equivalent Dose for Ptg-100, an Oral Peptide Antagonist of Integrin α4β7

PTG-100, a selective novel oral peptide antagonist of α4β7 integrin, is being developed for the treatment of patients with moderate to severe ulcerative colitis. PTG-100 alters trafficking of gut homing T cells in preclinical animal models, and its potency and selectivity are similar to that of the approved anti-α4β7 antibody vedolizumab. Pharmacokinetic studies in rodent or cynomolgus (cyno) monkeys show that PTG-100 exposure in the blood is <0.1% of dose, but >10% of dose in the small intestine and colon and up to 40% in feces, which indicate PTG-100 is orally stable and largely gut restricted. To help establish the potential efficacious dose range in humans, we developed a receptor occupancy assay to measure occupancy of CD4+ memory α4β7+ T cells in mouse blood and gastrointestinal (GI) tissues and in cyno blood. Daily dosing of PTG-100 and other similar antagonists in DSS (dextran sodium sulfate) treated mice showed a significant reduction in disease activity index (DAI), mucosal histopathology, and number of β7+ positive cells in the distal colon lesions. At these efficacious oral doses, α4β7 receptor occupancy in the blood, mesenteric lymph nodes, and Peyer’s Patches ranged from 46-81% at 4 h post dose. Single and multiple oral gavage administration of PTG-100 in healthy cynos showed that despite low systemic exposure, occupancy of blood α4β7 by PTG-100 is dose proportional, time-dependent, and influenced by the type of vehicle and fasted state of the animal. Allometric scaling from the mouse to human based on whole body surface area suggests that a similar level of blood receptor occupancy is associated with the cyno equivalent dose. The data suggests that 100% receptor occupancy over 24 h in the blood or GI in the mouse DSS model is not required for efficacy by an oral gut-restricted α4β7 antagonist. Together, these studies point to blood receptor occupancy and possibly receptor expression as useful clinical surrogates for the local effects of PTG-100 in the intestine. CONCLUSIONS