Structure-Based Identification of Ureas as Novel Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors

Abstract

Nicotinamide phosphoribosyltransferase (Nampt) is a promising anticancer target. Virtual screening identified a thiourea analogue, compound 5, as a novel highly potent Nampt inhibitor. Guided by the cocrystal structure of 5, SAR exploration revealed that the corresponding urea compound 7 exhibited similar potency with an improved solubility profile. These studies also indicated that a 3-pyridyl group was the preferred substituent at one inhibitor terminus and also identified a urea moiety as the optimal linker to the remainder of the inhibitor structure. Further SAR optimization of the other inhibitor terminus ultimately yielded compound 50 as a urea-containing Nampt inhibitor which exhibited excellent biochemical and cellular potency (enzyme IC50 = 0.007 μM; A2780 IC50 = 0.032 μM). Compound 50 also showed excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model (TGI of 97% was observed on day 17).

Discovery of potent and efficacious urea-containing nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with reduced CYP2C9 inhibition properties

“…7-10 We recently reported the structure-based identification of urea-containing NAMPT inhibitors exemplified by compounds 3 and 4 (Table 1). [11][12][13] While 3 and 4 exhibited many desirable biological properties, they were also potent (submicromolar), reversible inhibitors of the cytochrome P450 2C9 (CYP2C9) isozyme resulting in their potential to cause unwanted drug-drug interactions. 14 In this work, we describe our efforts to remove this unfavorable characteristic from this inhibitor series while retaining the desirable biopharmaceutical properties which existed in the lead compounds.…”

“…We therefore examined the introduction of additional terminal sulfonamides into the urea-containing inhibitor design that were not assessed during our initial explorations. 11 As shown in Table 3, compounds which terminated in substituted or bicyclic morpholine-derived sulfonamides exhibited relatively weak CYP2C9 inhibition properties (24-27). Further attenuation of the unwanted cytochrome P450 inhibition activity was achieved by employing terminal sulfonamides containing polar spirocyclic moieties (compounds 28-32, Table 3).…”

Development of CINPA1 analogs as novel and potent inverse agonists of constitutive androstane receptor

“…Chemical 51 was further converted to chemicals 36 and 37 by reacting with acyl chlorides of butyryl chloride and isopropyl chloroformate, respectively, in methylene chloride in the presence of triethylamine at 10°C to 35°C [41] and then converted to chemical 38 by reacting with di- tert -butyl dicarbonate under similar conditions [42]. To prepare chemicals 39 to 42 , chemical 51 was first activated into the form of imidazole carboxamide 52 with carbonyldiimidazole [43] in methylene chloride in the presence of triethylamine, and the chemical 52 was then converted to chemicals 39 to 42 by reacting with corresponding amines in methylene chloride in the presence of triethylamine and 4-dimethylaminopyridine [44].…”

“…The chloride chemical 78 was further converted to chemicals 65 – 72 by using different synthetic approaches. To prepare chemicals 65 and 66 , corresponding dipropylamine and piperidine groups were first alkylated with the chloride chemical 78 to form the intermediate chemicals 79 and 80 [32], which were then subjected to de-carboxybenzyl (de-Cbz) [48] with 10% Pd-C catalyzed hydrogenolysis in methanol at room temperature and acylation with di- tert -butyl dicarbonate [42] in methanol at room temperature to give respective target chemicals. To prepare chemical 67 , 2-propanol was first deprotonated with sodium at temperatures from 90°C to 60°C to form sodium isopropoxide, which was alkylated with the chloride chemical 78 to form the intermediate chemical 81 [49].…”

“…To prepare chemical 67 , 2-propanol was first deprotonated with sodium at temperatures from 90°C to 60°C to form sodium isopropoxide, which was alkylated with the chloride chemical 78 to form the intermediate chemical 81 [49]. The intermediate chemical 81 was then converted to chemical 67 [42] with di- tert -butyl dicarbonate in methanol at room temperature under 10% Pd-C-mediated catalytic hydrogenolysis conditions. During the preparation of chemicals 68 to 72 , pyrrole was de-protonated with sodium hydride in dimethylformamide at 0°C to 25°C under nitrogen atmosphere and then alkylated with the chloride chemical 78 to yield chemical 82 [50], which was then subjected to 10% Pd-C-mediated catalytic hydrogenolysis in ethyl acetate at room temperature to form chemical 83 [48], with the 3-amino group at the saturated dibezapine being available for further carbamation.…”