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Novel inhibitors of FXIa containing an (S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine core have been optimized to provide compound 16b, a potent, reversible inhibitor of FXIa (Ki = 0.3 nM) having in vivo antithrombotic efficacy in the rabbit AV-shunt thrombosis model (ID50 = 0.6 mg/kg + 1 mg kg(-1) h(-1)). Initial analog selection was informed by molecular modeling using compounds 11a and 11h overlaid onto the X-ray crystal structure of tetrahydroquinoline 3 complexed to FXIa. Further optimization was achieved by specific modifications derived from careful analysis of the X-ray crystal structure of the FXIa/11h complex. Compound 16b was well tolerated and enabled extensive pharmacologic evaluation of the FXIa mechanism up to the ID90 for thrombus inhibition.

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In an effort to identify novel antithrombotics, we have investigated protease-activated receptor 4 (PAR4) antagonism by developing and evaluating a tool compound, UDM-001651, in a monkey thrombosis model. Beginning with a high-throughput screening hit, we identified an imidazothiadiazole-based PAR4 antagonist chemotype. Detailed structure−activity relationship studies enabled optimization to a potent, selective, and orally bioavailable PAR4 antagonist, UDM-001651. UDM-001651 was evaluated in a monkey thrombosis model and shown to have robust antithrombotic efficacy and no prolongation of kidney bleeding time. This combination of excellent efficacy and safety margin strongly validates PAR4 antagonism as a promising antithrombotic mechanism.

Screening of a small set of nonselective lipase inhibitors against endothelial lipase (EL) identified a potent and reversible inhibitor, -(3-(3,4-dichlorophenyl)propyl)-3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (; EL IC = 61 nM, EL IC = 454 nM). Deck mining identified a related hit, -(3-(3,4-dichlorophenyl)propyl)-4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1-pyrrole-3-carboxamide (; EL IC = 41 nM, EL IC = 1760 nM). Both compounds were selective against lipoprotein lipase (LPL) but nonselective versus hepatic lipase (HL). Optimization of compound for EL inhibition using HDL as substrate led to-(4-(3,4dichlorophenyl)butan-2-yl)-1-ethyl-4-hydroxy-5-oxo-2,5-dihydro-1-pyrrole-3-carboxamide (; EL IC = 148 nM, EL IC = 218 nM) having improved PK over compound , providing a tool molecule to test for the ability to increase HDL-cholesterol (HDL-C) levels in vivo using a reversible EL inhibitor. Compound did not increase HDL-C in vivo despite achieving plasma exposures targeted on the basis of enzyme activity and protein binding demonstrating the need to develop more physiologically relevant in vitro assays to guide compound progression for in vivo evaluation.

A New Class of High Affinity Thyromimetics Containing a Phenyl-naphthyleneCore. -Based on modeling studies, a novel set of compounds such as (VII) and (XI) is prepared via the key synthetic step to (III). The structure-activity relationships are discussed in detail. A 25-fold selectivity for TRβ is observed for the most selective derivative (VII). The compounds may be a good starting point for further evaluations [for (XI) no yield given]. -(HANGELAND*, J. J.; FRIENDS, T. J.; DOWEYKO, A. M.; MELLSTROEM, K.; SANDBERG, J.; GRYNFARB, M.; RYONO, D. E.; Bioorg. Med. Chem. Lett. 15 (2005) 20, 4579-4584; Pharm. Res. Inst., Bristol-Myers Squibb Co., Princeton, NJ 08543, USA; Eng.) -K. Schneider 52-079

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