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Abstract: A co-crystal structure of amide-containing compound (4) in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein and molecular modeling were utilized to design and discover a potent novel cyanoguanidine-containing inhibitor bearing a sulfone moiety (5, Nampt Biochemical IC50 =2.5nM, A2780 cell proliferation IC50 =9.7nM). Further SAR exploration identified several additional cyanoguanidine-containing compounds with high potency and good microsomal stability. Among these, compound 15 was selected for in vivo profiling and demonstrated good oral exposure in mice. It also exhibited excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model. The co-crystal structure of this compound in complex with the NAMPT protein was also determined. [Copyright &y& Elsevier]

Abstract: The fragment-based identification of two novel and potent biochemical inhibitors of the nicotinamide phosphoribosyltransferase (NAMPT) enzyme is described. These compounds (51 and 63) incorporate an amide moiety derived from 3-aminopyridine, and are thus structurally distinct from other known anti-NAMPT agents. Each exhibits potent inhibition of NAMPT biochemical activity (IC50 =19 and 15nM, respectively) as well as robust antiproliferative properties in A2780 cell culture experiments (IC50 =121 and 99nM, respectively). However, additional biological studies indicate that only inhibitor 51 exerts its A2780 cell culture effects via a NAMPT-mediated mechanism. The crystal structures of both 51 and 63 in complex with NAMPT are also independently described. [Copyright &y& Elsevier]

Abstract: Potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitors containing 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas were identified using structure-based design techniques. The new compounds displayed improved aqueous solubilities, determined using a high-throughput solubility assessment, relative to previously disclosed urea and amide-containing NAMPT inhibitors. An optimized 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived compound exhibited potent anti-NAMPT activity (18; BC NAMPT IC50 =11nM; PC-3 antiproliferative IC50 =36nM), satisfactory mouse PK properties, and was efficacious in a PC-3 mouse xenograft model. The crystal structure of another optimized compound (29; NAMPT IC50 =10nM; A2780 antiproliferative IC50 =7nM) in complex with the NAMPT protein was also determined. [Copyright &y& Elsevier]

Crystal structures of several urea-and thiourea-derived compoundsin complex with the nicotinamide phosphoribosyltransferase (Nampt)protein were utilized to design a potent amide-containing inhibitorbearing an aza-indole moiety (7, Nampt BC IC50= 9.0 nM, A2780 cell proliferation IC50= 10 nM). TheNampt–7cocrystal structure was subsequently obtainedand enabled the design of additional amide-containing inhibitors whichincorporated various other fused 6,5-heterocyclic moieties and biarylsulfone or sulfonamide motifs. Additional modifications of these moleculesafforded many potent biaryl sulfone-containing Nampt inhibitors whichalso exhibited favorable in vitro ADME properties (microsomal andhepatocyte stability, MDCK permeability, plasma protein binding).An optimized compound (58) was a potent inhibitor ofmultiple cancer cell lines (IC50<10 nM vs U251, HT1080,PC3, MiaPaCa2, and HCT116 lines), displayed acceptable mouse PK properties(F = 41%, CL = 52.4 mL/min/kg), and exhibited robust efficacy in aU251 mouse xenograft model. [ABSTRACT FROM AUTHOR]

Nicotinamidephosphoribosyltransferase (Nampt) is a promising anticancertarget. Virtual screening identified a thiourea analogue, compound 5, as a novel highly potent Nampt inhibitor. Guided by thecocrystal structure of 5, SAR exploration revealed thatthe corresponding urea compound 7exhibited similar potencywith an improved solubility profile. These studies also indicatedthat a 3-pyridyl group was the preferred substituent at one inhibitorterminus and also identified a urea moiety as the optimal linker tothe remainder of the inhibitor structure. Further SAR optimizationof the other inhibitor terminus ultimately yielded compound 50as a urea-containing Nampt inhibitor which exhibited excellentbiochemical and cellular potency (enzyme IC50= 0.007 μM;A2780 IC50= 0.032 μM). Compound 50alsoshowed excellent in vivo antitumor efficacy when dosed orally in anA2780 ovarian tumor xenograft model (TGI of 97% was observed on day17). [ABSTRACT FROM AUTHOR]

Herein we report the optimization efforts to ameliorate the potent CYP3A4 time-dependent inhibition (TDI) and low aqueous solubility exhibited by a previously identified lead compound from our NAMPT inhibitor program ( 1 , GNE-617). Metabolite identification studies pinpointed the imidazopyridine moiety present in 1 as the likely source of the TDI signal, and replacement with other bicyclic systems was found to reduce or eliminate the TDI finding. A strategy of reducing the number of aromatic rings and/or lowering c Log D 7.4 was then employed to significantly improve aqueous solubility. These efforts culminated in the discovery of 42 , a compound with no evidence of TDI, improved aqueous solubility, and robust efficacy in tumor xenograft studies. [ABSTRACT FROM AUTHOR]

Potent, trans-2-(pyridin-3-yl)cyclopropanecarboxamide-containinginhibitors of the human nicotinamide phosphoribosyltransferase(NAMPT) enzyme were identified using fragment-based screening andstructure-based design techniques. Multiple crystal structures wereobtained of initial fragment leads, and this structural informationwas utilized to improve the biochemical and cell-based potency ofthe associated molecules. Many of the optimized compounds exhibitednanomolar antiproliferative activities against human tumor lines inin vitro cell culture experiments.In a key example, a fragment lead (13, KD= 51 μM) was elaborated into a potent NAMPT inhibitor(39, NAMPT IC50= 0.0051 μM, A2780 cellculture IC50= 0.000 49 μM) which demonstratedencouraging in vivo efficacy in an HT-1080 mouse xenograft tumor model. [ABSTRACT FROM AUTHOR]

Abstract: Potent, 1H-pyrazolo[3,4-b]pyridine-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using structure-based design techniques. Many of these compounds exhibited nanomolar antiproliferation activities against human tumor lines in in vitro cell culture experiments, and a representative example (compound 26) demonstrated encouraging in vivo efficacy in a mouse xenograft tumor model derived from the A2780 cell line. This molecule also exhibited reduced rat retinal exposures relative to a previously studied imidazo-pyridine-containing NAMPT inhibitor. Somewhat surprisingly, compound 26 was only weakly active in vitro against mouse and monkey tumor cell lines even though it was a potent inhibitor of NAMPT enzymes derived from these species. The compound also exhibited only minimal effects on in vivo NAD levels in mice, and these changes were considerably less profound than those produced by an imidazo-pyridine-containing NAMPT inhibitor. The crystal structures of compound 26 and the corresponding PRPP-derived ribose adduct in complex with NAMPT were also obtained. [Copyright &y& Elsevier]