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Structures and PC3 viability IC50 data for compounds in Figure 2.

Supplementary methods, tables S1-S3, and supplementary figures 1-7

Herein we disclose SAR studies that led to a series of isoindoline ureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. Modification of the isoindoline and/or the terminal functionality of screening hit 5 provided inhibitors such as 52 and 58 with nanomolar antiproliferative activity and preclinical pharmacokinetics properties which enabled potent antitumor activity when dosed orally in mouse xenograft models. X-ray crystal structures of two inhibitors bound in the NAMPT active-site are discussed.

Cancer cells are highly reliant on NAD+-dependent processes, including glucose metabolism, calcium signaling, DNA repair, and regulation of gene expression. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ salvage from nicotinamide, has been investigated as a target for anticancer therapy. Known NAMPT inhibitors with potent cell activity are composed of a nitrogen-containing aromatic group, which is phosphoribosylated by the enzyme. Here, we identified two novel types of NAM-competitive NAMPT inhibitors, only one of which contains a modifiable, aromatic nitrogen that could be a phosphoribosyl acceptor. Both types of compound effectively deplete cellular NAD+, and subsequently ATP, and produce cell death when NAMPT is inhibited in cultured cells for more than 48 hours. Careful characterization of the kinetics of NAMPT inhibition in vivo allowed us to optimize dosing to produce sufficient NAD+ depletion over time that resulted in efficacy in an HCT116 xenograft model. Our data demonstrate that direct phosphoribosylation of competitive inhibitors by the NAMPT enzyme is not required for potent in vitro cellular activity or in vivo antitumor efficacy. Mol Cancer Ther; 16(7); 1236–45. ©2017 AACR.

Potent and selective adamantane sulfone and sulfonamide inhibitors of 11-beta-HSD-1 have been discovered. Selected compounds from these series have robust pharmacokinetic profiles and strongly inhibit liver, fat, and brain HSD1 for extended periods after oral dosing.

Starting from a rapidly metabolized adamantane 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor 22a, a series of E-5-hydroxy-2-adamantamine inhibitors, exemplified by 22d and (+/-)-22f, was discovered. Many of these compounds are potent inhibitors of 11beta-HSD1 and are selective over 11beta-HSD2 for multiple species (human, mouse, and rat), unlike other reported species-selective series. These compounds have good cellular potency and improved microsomal stability. Pharmacokinetic profiling in rodents indicated moderate to large volumes of distribution, short half-lives, and a pharmacokinetic species difference with the greatest exposure measured in rat with 22d. One hour postdose liver, adipose, and brain tissue 11beta-HSD1 inhibition was confirmed with (+/-)-22f in a murine ex vivo assay. Although 5,7-disubstitued-2-adamantamines provided greater stability, a single, E-5-position, polar functional group afforded inhibitors with the best combination of stability, potency, and selectivity. These results indicate that adamantane metabolic stabilization sufficient to obtain short-acting, potent, and selective 11beta-HSD1 inhibitors has been discovered.

High throughput screening efforts have identified a novel class of dichloroaniline amide 11beta-HSD1 inhibitors. SAR studies initiated from dichloroaniline 4 focused on retaining the potency and selectivity profile of the lead.

Bile acid conjugates of a selective nonsteroidal glucocorticoid receptor modulator were prepared and evaluated. Potent GR binding conjugates that showed improved metabolic stability were discovered. However, cellular potency and pharmacokinetics were not substantially improved.

The optimization of a series of nonsteroidal glucocorticoid modulators is reported. Potent selective GR ligands that have improved metabolic stability were discovered typified by the subnanomolar acid 12 (GR binding IC 50 = 0.6 nM).

Diarylsulfide cyclopropylamides were synthesized and evaluated as LFA-1/ICAM-1 interaction antagonists. A substituent pattern was identified which maximized potency and minimized protein binding as exemplified by antagonist 30 (IC 50 =5 nM).

Johnson's Suzuki coupling protocol was employed to prepare C -glycoside analogs of phlorizin ( 1 ). In vitro biological evaluation of these C -glycosides indicated the anomeric oxygen is important to the SGLT inhibitory activity of phlorizin ( 1 ) and related agents.

The synthesis and evaluation of analogues of previously reported farnesyltransferase inhibitors, pyridyl benzyl ether 3 and pyridylbenzylamine 4, are described. Substitution of 3 at the 5-position of the core aryl ring resulted in inhibitors of equal or less potency against the enzyme and decreased efficacy in a cellular assay against Ras processing by the enzyme. Substitution of 4 at the benzyl nitrogen yielded 26, which showed improved efficacy and potency and yet presented a poor pharmacokinetic profile. Further modification afforded 30, which demonstrated a dramatically improved pharmacokinetic profile. Compounds 26 and 29 demonstrated significant in vivo efficacy in nude mice inoculated with MiaPaCa-2, a human pancreatic tumor-derived cell line.

Endothelins, ET-1, ET-2, and ET-3 are potent vasoconstricting and mitogenic 21-amino acid bicyclic peptides, which exert their effects upon binding to the ET A and ET B receptors. The ET A receptor mediates vasoconstriction and smooth muscle cell proliferation, and the ET B receptor mediates different effects in different tissues, including nitric oxide release from endothelial cells, and vasoconstriction in certain vascular cell types. Selective antagonists of endothelin receptor subtypes may prove useful in determining the role of endothelin in various tissue types and disease states, and hence as therapeutic agents for such diseases. The pyrrolidine carboxylic acid A-127722 has been disclosed as a potent and ET A -selective antagonist, and is currently undergoing clinical trials. In our efforts to find antagonists with altered selectivity (ET A -selective, ET B -selective, or nonselective), we investigated the SAR of the 2-substituent on the pyrrolidine. Compounds with alkyl groups at the 2-position possessed ET A selectivity improved over A-127722 (1400-fold selective), with the best of these compounds showing nearly 19,000-fold selectivity.

The benzodioxole ((methylenedioxy)benzene) group is present in a number of endothelin (ET) receptor antagonists thus far reported. As part of our own endothelin antagonist program we have developed (2R*,3R*,4S*)-1-(N,N-dibutylacetamido)-4-(1,3-benzodioxol-5- yl)-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid (A-127722). This is a potent antagonist, binding to the ETA and ETB receptor subtypes with affinities (IC50) of 0.4 and 520 nM, respectively, and also contains the aforementioned benzodioxole. While this compound was seemingly optimized at its N-terminus, no effort had been directed toward understanding the contributions to binding affinity or receptor subtype selectivity conferred by the benzodioxole. Substitution by 1- or 2-naphthyl yielded weak antagonists. Oxygenated benzenes, such as p-anisyl, were potent compounds with IC50s in the low-nanomolar range. Simple deletion of either of the two oxygen atoms (dihydrobenzofurans) yielded extremely potent agents, possessing subnanomolar affinity for the ETA receptor. Additionally, the compounds showed enhanced selectivity, binding to the ETB receptor subtype in the micromolar range. This paper describes the development of this novel class of compounds.

Fused ring heterocyclic analogs of A-81080 (pA2= 9.9) were synthesized and their activities in the rabbit aorta in vitro assay were measued. The best compounds (pA2 = 8.6) in series 1 had R1 = Et, R2 = H, W = X = Z = C-H, and Y = C-OMe or C-COOH. In series 2, the best compound (pA2 = 8.3) had R1 = Et, R2 = H, W = N-Me, X = C-H, and Y = N.

The facile preparation of 2-butyl-4-iodoimidazole-5-carboxaldehyde 1 is described. The versatility of this intermediate in the synthesis of highly tunctionalized imidazoles is demonstrated with the synthesis of two potent and selective angiotensin II receptor antagonists.

Diarylsulfide cyclopropylamides were synthesized and evaluated as LFA-1/ICAM-1 interaction antagonists. A substituent pattern was identified which maximized potency and minimized protein binding as exemplified by antagonist 30 (IC 50 =5 nM).

The design and enzyme activities of a novel class of imidazo[2,1-b]thiazoles is presented.

A series of potent and selective adamantane aminoamide 11-β-HSD-1 inhibitors has been optimized. Chemically these studies were expedited by utilizing readily obtained amino acids as starting materials or an isocyanide multicomponent reaction. Structure–activity relationship studies resulted in the discovery of dual human and mouse 11-β-HSD-1 potent and selective inhibitors like adamantane 11 and related compounds with high metabolic stability and robust pharmacokinetic profiles.

A new class of selective nonsteroidal glucocorticoid receptor modulators typified by N-{3-[benzyl-(4-chloro-2-fluoro-benzyl)-amino]-2-methyl-phenyl}-methanesulfonamide 19 has been discovered.

The synthesis, activity, metabolic stability, and pharmacokinetics of steroidal and nonsteroidal glucocorticoid receptor modulator–statin hybrids is reported. Potent steroidal antagonist–statin hybrids like 22 (h-GR binding IC 50 =7 nM) and nonsteroidal modulator hybrids like 16 (h-GR binding IC 50 =2 nM) were discovered. Appending a `statin'-like diol-acid group to the modulators dramatically improved metabolic stability (and in some cases hepatocyte activity), but did not impart hepatoselectivity.

Biaryl amides derived from a reported series of ureas 1 were evaluated and found to be potent human glucagon receptor antagonists. The benzofuran analogue 6i was administered in Sprague-Dawley rats and blocked the effects of an exogenous glucagon challenge.

The synthesis and structure-activity relationships (SAR) of a series of pyrrolidine-3-carboxylic acids as endothelin antagonists are described. The data shows an increase in selectivity when the methoxy of Atrasentan (ABT-627) is replaced with methyl, and the benzodioxole is replaced with dihydrobenzofuran. Adding a fluorine further increases the binding activity and provides a metabolically stable and orally bioavailable ET(A)-selective antagonist.

Abbott-81988 (A-81988), 2-(N-n-Propyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4- yl)methyl]amino)pyridine-3-carboxylic acid is a potent, competitive, non-peptidic antagonist of angiotensin AT1 receptors. A-81988 was labeled with tritium to high specific activity (16 Ci/mmol) and radioligand binding assays performed in rat liver membranes. [3H]A-81988 bound with high affinity (KD = 0.57 nM) and the KD determined from kinetics assays was similar. Non-specific binding (defined with 10(-6) M angiotensin-II) was very low (< 6% at the KD). The binding of [3H]A-81988 was competitive and exhibited appropriate pharmacological specificity for compounds acting at angiotensin AT1 receptors. These properties demonstrate that [3H]A-81988 will be a useful radioligand for studies of angiotensin AT1 receptors in various tissues.

The insulin-like growth factor 1 receptor (IGF1R) and its ligands, IGF1 and IGF2 are associated with cell growth and resistance to apoptosis. The ErbB axis, consisting of 4 receptor tyrosine kinases (EGFR, ErbB2, ErbB3, and ErbB4) is a longstanding target of cancer chemotherapy. There is a growing body of literature suggesting that targeting a combination of the IGF and ErbB axes would be more effective than targeting either alone. A screen of Abbott's compound collection revealed a scaffold, the imidazothiazoles, which showed activity against EGFR. A similar scaffold from the literature had previously been reported to have IGF1R activity. Optimization of the imidazothiazoles, and a scaffold hop to imidazopyridines, has provided a series of compounds with amide head groups with kinase inhibitory activity against IGF1R, EGFR, and ErbB2. These compounds also demonstrated inhibition of p-IGF1R and p-EGFR in a human epidermoid carcinoma line (A-431), as well as inhibition of p-ErbB2 in a human gastric cancer cell line (N87). This poster will discuss the synthesis and optimization of the imidazothiazoles and imidazopyridines as multitargeted kinase inhibitors. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A245.