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This review provides an overview of stearoyl-coenzyme A desaturase-1 (SCD1) as a novel therapeutic target for metabolic disorders and other indications. Target validation is reviewed, and limitations due to incomplete knowledge of the relevant biological systems are described. Assay development, particularly for high throughput screening, and characterization of SCD1 inhibition are summarized. The progress and evolution in medicinal chemistry are discussed, specifically focusing on key attributes of the most advanced SCD1 inhibitors described in the primary literature and in patent applications. This work culminated in numerous companies identifying potent selective inhibitors, some of which progressed to early clinical development. The status of current SCD1 drug discovery programs is reviewed. Challenges are discussed, and potential new directions are indicated.

This paper is dedicated to the memory of Professor Thotnas BirchallZAIHUI ZHANG, STEVEN J. RETTIG, and CHRIS ORVIG. Can. J. Chem. 70, 763 (1992). 3-Hydroxy-I-carboxymethyl-2-methyl-4-pyridinone (Hcmp) and 3-hydroxy-I-(p-rnethoxypheny1)-2-methyl-4-pyridine (Hpap) have been prepared and studie! by single crystal X-ray diffraction. Crystals of Hcmp are monoclinic, a = 6.340 (2), b = 7.705 (I), c = 16.226 (1) A, P = 94.74 (I), Z = 4, space group P 2 , / n and those for Hpap are monoclinic, a = 10.8435 (9), b = 16.680 (2), c = 13.5665 (6) A, P = 109.450 (4), Z = 8, space group C 2 / c . Both structures were solved by direct methods and were refined by full-matrix least-squares procedures to R = 0.030 and 0.041 (R,, = 0.039 and 0.058) for 1642 and 1819 reflections with I 2 3u(I), respectively. Bond lengths and bond angles in the two compounds are normal; however, Hcmp forms as a zwitterion in the solld state. The two compounds were also studied by mass spectrometry, UV, infrared, proton NMR spectroscopies, and potentiometric equllibnum measurements. The protonation constants for Hcrnp are log Kl = 9.76 (I), log K2 = 3.43 (I), and log K, = 2.78 (3) and for Hpap are log K ; = 9.42 (4) and log K ; = 3.16 (8).Key words: 3-hydroxy-4-pyridinone, zwitterion, hydrogen bonding, protonation constant, crystallography, solid state. Introduction N-aryl (2) substituted-3-hydroxy-2-methyl-4-pyridinones and AS part of our project to examine the coordination themtheir metal complexes have been reported (7,8). he studistry and biochemical properties of aluminum, gallium, and ies have shown that these complexes have unique Properindium complexes, we have been studying tris(ligand) cornties: reasonable water solubility, variable lipophilicity, high plexes of these metal ions with 3-hydroxy-4-pyrones (1 -3) thermodynamic stability, and interesting biological activity and 3-hydroxy-4-pyridinones (4-7) as bidentate ligands. The (7, 9-1 1). preparation and characterization of a series of N-alkyl (1) and

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