Selective CB2 receptor agonists are promising potential therapeutic agents for the treatment of inflammatory and neuropathic pain. A focused screen identified a pyrimidine ester as a partial agonist at the CB2 receptor with micromolar potency. Subsequent lead optimization identified 35, GW842166X, as the optimal compound in the series. 35 has an oral ED50 of 0.1 mg/kg in the rat FCA model of inflammatory pain and was selected as a clinical candidate for this indication.

The stable, readily available molybdenum(II) complexes [Mo(CO)(4)Br(2)](2) (B) and Mo(CO)(3)(MeCN)(2)(SnCl(3))Cl (C) have been found to catalyze C-C bond-forming allylic substitution with electron-rich aromatics (e.g., 15 + PhOMe --> 62) and heteroaromatics (e.g., 15 + 36 --> 88) as nucleophiles under mild conditions (room temperature, 30 min-3 h). Remarkable is the para-selectivity for anisole, whereas phenol tends to favor ortho-substitution in certain instances. Mechanistic and stereochemical experiments are indicative of Lewis-acid catalysis rather than a metal template-controlled process.

We report on the development of a series of pyrimidine carboxylic acids that are potent and selective inhibitors of kynurenine monooxygenase and competitive for kynurenine. We describe the SAR for this novel series and report on their inhibition of KMO activity in biochemical and cellular assays and their selectivity against other kynurenine pathway enzymes. We describe the optimization process that led to the identification of a program lead compound with a suitable ADME/PK profile for therapeutic development. We demonstrate that systemic inhibition of KMO in vivo with this lead compound provides pharmacodynamic evidence for modulation of kynurenine pathway metabolites both in the periphery and in the central nervous system.

c = 17.0760(3) A gamma = 99.3550(11) deg. Volume 2395.20(7) A^3 Z, Calculated density 6, 1.511 Mg/m^3 Absorption coefficient 2.576 mm^-1 F(000) 1104 Crystal size 0.5 x 0.4 x 0.2 mm Theta range for data collection 3.19 to 25.07 deg. Limiting indices -11<=h<=11, -18<=k<=18, -19<=l<=20 Reflections collected / unique 34246 / 8418 [R(int) = 0.0594] Completeness to theta = 25.07 99.0 % Absorption correction Multiscan Max. and min. transmission 0.598 and 0.415 Refinement method Full-matrix least-squares on F^2 Data / restraints / parameters 8418 / 0 / 802 Goodness-of-fit on F^2 0.993 Final R indices [I>2sigma(I)] R1 = 0.0335, wR2 = 0.0850 R indices (all data) R1 = 0.0397, wR2 = 0.0900 Largest diff. peak and hole 0.561 and -0.753 e.A^-3Table 3. Bond lengths [A] and angles [deg] for (±)-18. _____________________________________________________________ Br(1)-C(18') 1.913(2) C(11)-C(12) 1.380(4) C(11)-C(19) 1.426(3) C(11)-C(11') 1.499(3) C(12)-O(1) 1.374(3) C(12)-C(13) 1.411(4) C(13)-C(14) 1.370(4) C(13)-H(13) 0.94(3) C(14)-C(110) 1.405(4) C(14)-H(14) 0.96(3) C(15)-C(16) 1.362(4) C(15)-C(110) 1.422(4) C(15)-H(15) 0.97(3) C(16)-C(17) 1.411(4) C(16)-H(16) 0.94(3) C(17)-C(18) 1.366(4) C(17)-H(17) 0.90(3) C(18)-C(19) 1.421(4) C(18)-H(18) 0.93(3) C(19)-C(110) 1.430(3) C(11')-C(12') 1.384(4) C(11')-C(19') 1.433(4) C(12')-C(13') 1.407(4) C(12')-H(12') 0.88(3) C(13')-C(14') 1.360(4) C(13')-H(13') 0.88(3) C(14')-C(10') 1.414(4) C(14')-H(14') 0.92(3) C(15')-C(16') 1.351(4) C(15')-C(10') 1.425(4) C(15')-H(15') 0.91(3) C(16')-C(17') 1.409(4) C(16')-H(16') 0.97(3) C(17')-C(18') 1.369(4) C(17')-H(17') 0.94(3) C(18')-C(19') 1.428(4) C(19')-C(10') 1.444(3) O(1)-C(1) 1.425(3) C(1)-H(1A) 0.97(3) C(1)-H(1B) 0.97(4) C(1)-H(1C) 0.93(3) Br(2)-C(28') 1.914(3) C(21)-C(22) 1.383(4) C(21)-C(29) 1.422(4) C') 1.422(4) C(25')-H(25') 0.91(3) C(26')-C(27') 1.405(4) C(26')-H(26') 0.97(4) C(27')-C(28') 1.370(4) C(27')-H(27') 0.98(3) C(28')-C(29') 1.428(4) C(29')-C(20') 1.438(4) O(2)-C(2) 1.431(3) C(2)-H(2A) 0.98(3) C(2)-H(2B) 0.94(4) C(2)-H(2C) 1.07(4) Br(3)-C(38') 1.915(3) C(31)-C(32) 1.384(4) C(31)-C(39) 1.421(4) C(31)-C(31') 1.500(3) C(32)-O(3) 1.370(3) C(32)-C(33) 1.412(4) C(33)-C(34) 1.359(4) C(33)-H(33) 0.96(4) C(34)-C(310) 1.412(4) C(34)-H(34) 0.95(3) C(35)-C(36) 1.362(4) C(35)-C(310) 1.414(4) C(35)-H(35) 0.97(3) C(36)-C(37) 1.412(4) C(36)-H(36) 0.98(3) C(37)-C(38) 1.366(4) C(37)-H(37) 0.93(3) C(38)-C(39) 1.420(4) C(38)-H(38) 0.98(4) C(39)-C(310) 1.432(4) C(31')-C(32') 1.382(4) C(31')-C(39') 1.427(4) C(32')-C(33') 1.408(4) C(32')-H(32') 0.85(3) C(33')-C(34') 1.351(4) C(33')-H(33') 1.01(3) C(34')-C(30') 1.419(4) C(34')-H(34') 0.95(3) C(35')-C(36') 1.359(4) C(35')-C(30') 1.423(4) C(35')-H(35') 0.97(3) C(36')-C(37') 1.407(4) C(36')-H(36') 0.93(3) C(37')-C(38') 1.365(4) C(37')-H(37') 0.90(3) C(38')-C(39') 1.430(4) C(39')-C(30') 1.440(3) O(3)-C(3) 1.432(4) C(3)-H(3A) 0.99(4) C(3)-H(3B) 0.98(3) C(3)-H(3C) Table 12. Torsion angles [deg] for (S)-(+)-18. ________________________________________________________________ C(1)-O(1)-C(12)-C(11) 177.2(4) C(1)-O(1)...