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    • Given the excellent in vitro pharmacology profiles

    2020-04-22

    Given the excellent in vitro pharmacology profiles of methyl ester 28 and primary amide 29 efforts were reengaged on neutral analogs of these leads, with a focus on non-amide replacements for the carboxylic saquinavir receptor functionality of 1. Acetonitrile 49 was found to have a good balance of DGAT-1 inhibitory activity, microsomal stability and passive permeability (Table 6). Incorporation of a tertiary alcohol (50) is also well tolerated in terms of suppression of DGAT-1 activity, microsomal clearance and passive permeability. Though not neutral under physiological conditions, it is worth noting that the corresponding tertiary basic amine 51 retains good DGAT-1 potency, however, it suffers from poor passive permeability. Both 49 and 50 were evaluated in rat pharmacokinetic analyses and based on the relative profiles, the latter was advanced to a rat safety evaluation. In-life and clinical pathology analyses of Sprague-Dawley rats treated for four days with oral doses (5, 50 and 500mg/kg) of 50 revealed a number of side effects at the mid and high doses. These included skin turgor, reductions in body weight, increases in serum cholesterol and decreased T4 hormone levels. These results led us to consider other options for neutral replacements of the carboxylic acid moiety of 1. Given the well established ability of azoles to serve as bioisosteric replacements for amides and esters, a series of five-membered heterocycle-based analogs were pursued. 1,2,4-Oxadiazole 52 was found to be a potent inhibitor of DGAT-1 and cellular triglyceride synthesis. Its balanced physicochemical properties (LogD=2.3, PSA=120) resulted in an excellent ADME profile with low microsomal clearance (<8mL/min/kg) and high passive permeability (39×10−6cm/s). Alternative oxadiazole, thiadiazole and triazole motifs (53–56) were found to have both reduced DGAT-1 inhibitory activities and passive permeabilities. Given the profile of oxadiazole 52 the corresponding homologated analog 57 was evaluated. While incorporation of an additional methylene unit had no significant impact on DGAT-1 inhibitory activity relative to 52, it was found to have substantially reduced metabolic stability (HLM CLapp=82mL/min/kg). From this set of neutral heterocyclic-based analogs, oxadiazole 52 was selected for further pharmacokinetic, safety and efficacy profiling. Pharmacokinetic profiling in rat revealed 52 to have low clearance (5.3mL/min/kg) and moderate oral bioavailability of 53% (Fig. 4). These data in combination with the low turnover in human microsomes predict an attractive pharmacokinetic profile in humans. Compound 52 was very selective versus the closet DGAT-1 enzymatic family members hACAT-1 and hDGAT-2 (Fig. 7). The risk of off-target pharmacology presenting a safety issue for 52 appeared to be minimal based on selectivity indices of >150-fold for a panel of 140 human receptors and channels. Negative results in Ames and in vitro micronucleus analyses suggested low genetic toxicology risk for this compound. No detectable inhibition against a panel of human cytochrome P-450 isoforms indicated low probability of drug–drug interactions in the human clinical setting. Patch clamp analysis of the potential hERG liability 52 revealed an IC50 >30μM. Based on this in vitro safety profile, 52 was advanced to a four day rat safety evaluation at doses of 5, 50 and 500mg/kg (po). No significant clinical signs, changes in body/liver weights or histology/hematological endpoints were observed at all doses. The only findings were slight elevations in total cholesterol (1.5-fold), total triiodothyronine levels (1.3-fold, with no impact on thyroxine or thyroid-stimulating hormone) and liver enzymes (ALT, 1.5-fold) at 500mg/kg. Based on this encouraging safety profile, compound 52 was advanced to acute and chronic in vivo efficacy evaluations (Table 7). The pharmacodynamic potential of compound 52 was initially evaluated in an oral triglyceride tolerance test. C57BL/6 mice were treated with vehicle, 0.1, 0.3 or 1mg/kg of 52 30min prior to dosing with a corn oil bolus. Plasma triglyceride (TG) levels were monitored every hour over the course of the 4h test period. Compound 52 inhibited the increase in plasma TG levels in a dose dependent manner, with complete suppression of TG excursion at a dose of 0.3mg/kg (Fig. 2). These results compared favorably with what is seen for the lead clinical candidate 1, which exhibits a comparable potency in this assay.