The Mn(II) and Mn(III) complexes of the pentadentate ligand N,N-bis(2-pyridylmethyl)amine-N-ethyl-2-pyridine-2-carboxamide (PaPy3H; H is the dissociable carboxamide H), namely, [Mn(PaPy3)(H2O)]ClO4 (1) and [Mn(PaPy3)(Cl)]ClO4 (2), with bound carboxamido nitrogen have been isolated and characterized. The high-spin Mn(II) center in 1 is very sensitive to dioxygen, and this complex is rapidly converted into 2 upon reaction with Cl- in air. The bound carboxamido nitrogen in 1 is responsible for this sensitivity toward oxidation since the analogous Schiff base complex [Mn(SBPy3)Cl]ClO4 (4) is very resistant to oxidation. Reaction of NO with 1 affords the diamagnetic [Mn-NO]6 nitrosyl [Mn(PaPy3)(NO)]ClO4 (5). Complexes with no bound carboxamido nitrogen such as 4 and [Mn(PaPy3H)(Cl)2] (3) do not react with NO. No reaction with NO is observed with the Mn(III) complexes 2 and [Mn(PaPy3)(MeCN)]2+ either. Collectively these reactions indicate that NO reacts only with the Mn(II) center ligated to at least one carboxamido nitrogen. Both the carbonyl and N-O stretching frequencies (nu(CO) and nu(NO)) of the present and related complexes strongly suggest a [low-spin Mn(II)-NO*] formulation for 5. The alternative description [low-spin Mn(I)-NO+] is not supported by the spectroscopic and redox behavior of 5. Complex 5 is the first example of a [Mn-NO]6 nitrosyl that exhibits photolability of NO upon illumination with low-intensity tungsten lamps in solvents such as MeCN and H2O. The rapid NO loss from 5 leads to the formation of the corresponding solvato species [Mn(PaPy3)(MeCN)]2+ under aerobic conditions. Oxidation of 5 with (NH4)2[Ce(NO3)6] in MeCN affords the highly reactive paramagnetic (S = 1/2) [MnNO]5 nitrosyl [Mn(PaPy3)(NO)](NO3)2 (6) in high yield. Spectroscopic and magnetic studies confirm a [low-spin Mn(II)-NO+] formulation for 6. The N-O stretching frequencies (nu(NO)) of 5, 6, and analogous nitrosyls reported by other groups collectively suggest that nu(NO) is a better indicator of the oxidation state of NO (NO+, NO*, or NO-) in non-heme iron and other transition-metal complexes with bound NO.

We started with a medium throughput screen of heterocyclic compounds without basic amine groups to avoid hERG and β-blocker activity and identified [1,2,4]triazolo[4,3-a]pyridine as an early lead. Optimization of substituents for Late INa current inhibition and lack of Peak INa inhibition led to the discovery of 4h (GS-458967) with improved anti-arrhythmic activity relative to ranolazine. Unfortunately, 4h demonstrated use dependent block across the sodium isoforms including the central and peripheral nervous system isoforms that is consistent with its low therapeutic index (approximately 5-fold in rat, 3-fold in dog). Compound 4h represents our initial foray into a 2nd generation Late INa inhibitor program and is an important proof-of-concept compound. We will provide additional reports on addressing the CNS challenge in a follow-up communication.

Chorismate-utilizing enzymes are attractive antimicrobial drug targets due to their absence in humans and their central role in bacterial survival and virulence. The structural and mechanistic homology of a group of these inspired the goal of discovering inhibitors that target multiple enzymes. Previously, we discovered seven inhibitors of 4-amino-4-deoxychorismate synthase (ADCS) in an on-bead, fluorescent-based screen of a 2304-member one-bead-one-compound combinatorial library. The inhibitors comprise PAYLOAD and COMBI stages, which interact with active site and surface residues, respectively, and are linked by a SPACER stage. These seven compounds, and six derivatives thereof, also inhibit two other enzymes in this family, isochorismate synthase (IS) and anthranilate synthase (AS). The best binding compound inhibits ADCS, IS, and AS with K(i) values of 720, 56, and 80 microM, respectively. Inhibitors with varying SPACER lengths show the original choice of lysine to be optimal. Lastly, inhibition data confirm the PAYLOAD stage directs the inhibitors to the ADCS active site.

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