Lai JH

References (13)

Title : Preclinical Development of PNT6555, a Boronic Acid-Based, Fibroblast Activation Protein-alpha (FAP)-Targeted Radiotheranostic for Imaging and Treatment of FAP-Positive Tumors - Poplawski_2023_J.Nucl.Med__
Author(s) : Poplawski SE , Hallett RM , Dornan MH , Novakowski KE , Pan S , Belanger AP , Nguyen QD , Wu W , Felten AE , Liu Y , Ahn SH , Hergott VS , Jones B , Lai JH , McCann JAB , Bachovchin WW
Ref : J Nucl Med , : , 2023
Abstract : The overexpression of fibroblast activation protein-alpha (FAP) in solid cancers relative to levels in normal tissues has led to its recognition as a target for delivering agents directly to tumors. Radiolabeled quinoline-based FAP ligands have established clinical feasibility for tumor imaging, but their therapeutic potential is limited due to suboptimal tumor retention, which has prompted the search for alternative pharmacophores. One such pharmacophore is the boronic acid derivative N-(pyridine-4-carbonyl)-d-Ala-boroPro, a potent and selective FAP inhibitor (FAPI). In this study, the diagnostic and therapeutic (theranostic) potential of N-(pyridine-4-carbonyl)-d-Ala-boroPro-based metal-chelating DOTA-FAPIs was evaluated. Methods: Three DOTA-FAPIs, PNT6555, PNT6952, and PNT6522, were synthesized and characterized with respect to potency and selectivity toward soluble and cell membrane FAP; cellular uptake of the Lu-chelated analogs; biodistribution and pharmacokinetics in mice xenografted with human embryonic kidney cell-derived tumors expressing mouse FAP; the diagnostic potential of (68)Ga-chelated DOTA-FAPIs by direct organ assay and small-animal PET; the antitumor activity of (177)Lu-, (225)Ac-, or (161)Tb-chelated analogs using human embryonic kidney cell-derived tumors expressing mouse FAP; and the tumor-selective delivery of (177)Lu-chelated DOTA-FAPIs via direct organ assay and SPECT. Results: DOTA-FAPIs and their (nat)Ga and (nat)Lu chelates exhibited potent inhibition of human and mouse sources of FAP and greatly reduced activity toward closely related prolyl endopeptidase and dipeptidyl peptidase 4. (68)Ga-PNT6555 and (68)Ga-PNT6952 showed rapid renal clearance and continuous accumulation in tumors, resulting in tumor-selective exposure at 60 min after administration. (177)Lu-PNT6555 was distinguished from (177)Lu-PNT6952 and (177)Lu-PNT6522 by significantly higher tumor accumulation over 168 h. In therapeutic studies, all 3 (177)Lu-DOTA-FAPIs exhibited significant antitumor activity at well-tolerated doses, with (177)Lu-PNT6555 producing the greatest tumor growth delay and animal survival. (225)Ac-PNT6555 and (161)Tb-PNT6555 were similarly efficacious, producing 80% and 100% survival at optimal doses, respectively. Conclusion: PNT6555 has potential for clinical translation as a theranostic agent in FAP-positive cancer.
ESTHER : Poplawski_2023_J.Nucl.Med__
PubMedSearch : Poplawski_2023_J.Nucl.Med__
PubMedID: 38050111

Title : Fibroblast activation protein is dispensable for control of glucose homeostasis and body weight in mice - Panaro_2019_Mol.Metab_19_65
Author(s) : Panaro BL , Coppage AL , Beaudry JL , Varin EM , Kaur K , Lai JH , Wu W , Liu Y , Bachovchin WW , Drucker DJ
Ref : Mol Metab , 19 :65 , 2019
Abstract : OBJECTIVE: Fibroblast Activation Protein (FAP), an enzyme structurally related to dipeptidyl peptidase-4 (DPP-4), has garnered interest as a potential metabolic drug target due to its ability to cleave and inactivate FGF-21 as well as other peptide substrates. Here we investigated the metabolic importance of FAP for control of body weight and glucose homeostasis in regular chow-fed and high fat diet-fed mice. METHODS: FAP enzyme activity was transiently attenuated using a highly-specific inhibitor CPD60 and permanently ablated by genetic inactivation of the mouse Fap gene. We also assessed the FAP-dependence of CPD60 and talabostat (Val-boroPro), a chemical inhibitor reportedly targeting both FAP and dipeptidyl peptidase-4 RESULTS: CPD60 robustly inhibited plasma FAP activity with no effect on DPP-4 activity. Fap gene disruption was confirmed by assessment of genomic DNA, and loss of FAP enzyme activity in plasma and tissues. CPD60 did not improve lipid tolerance but modestly improved acute oral and intraperitoneal glucose tolerance in a FAP-dependent manner. Genetic inactivation of Fap did not improve glucose or lipid tolerance nor confer resistance to weight gain in male or female Fap(-/-) mice fed regular chow or high-fat diets. Moreover, talabostat markedly improved glucose homeostasis in a FAP- and FGF-21-independent, DPP-4 dependent manner. CONCLUSION: Although pharmacological FAP inhibition improves glucose tolerance, the absence of a metabolic phenotype in Fap(-/-)mice suggest that endogenous FAP is dispensable for the regulation of murine glucose homeostasis and body weight. These findings highlight the importance of characterizing the specificity and actions of FAP inhibitors in different species and raise important questions about the feasibility of mouse models for targeting FAP as a treatment for diabetes and related metabolic disorders.
ESTHER : Panaro_2019_Mol.Metab_19_65
PubMedSearch : Panaro_2019_Mol.Metab_19_65
PubMedID: 30477988

Title : DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis - Okondo_2017_Nat.Chem.Biol_13_46
Author(s) : Okondo MC , Johnson DC , Sridharan R , Go EB , Chui AJ , Wang MS , Poplawski SE , Wu W , Liu Y , Lai JH , Sanford DG , Arciprete MO , Golub TR , Bachovchin WW , Bachovchin DA
Ref : Nat Chemical Biology , 13 :46 , 2017
Abstract : Val-boroPro (Talabostat, PT-100), a nonselective inhibitor of post-proline cleaving serine proteases, stimulates mammalian immune systems through an unknown mechanism of action. Despite this lack of mechanistic understanding, Val-boroPro has attracted substantial interest as a potential anticancer agent, reaching phase 3 trials in humans. Here we show that Val-boroPro stimulates the immune system by triggering a proinflammatory form of cell death in monocytes and macrophages known as pyroptosis. We demonstrate that the inhibition of two serine proteases, DPP8 and DPP9, activates the pro-protein form of caspase-1 independent of the inflammasome adaptor ASC. Activated pro-caspase-1 does not efficiently process itself or IL-1beta but does cleave and activate gasdermin D to induce pyroptosis. Mice lacking caspase-1 do not show immune stimulation after treatment with Val-boroPro. Our data identify what is to our knowledge the first small molecule that induces pyroptosis and reveals a new checkpoint that controls the activation of the innate immune system.
ESTHER : Okondo_2017_Nat.Chem.Biol_13_46
PubMedSearch : Okondo_2017_Nat.Chem.Biol_13_46
PubMedID: 27820798
Gene_locus related to this paper: human-DPP8 , human-DPP9

Title : (-)-Phenserine inhibits neuronal apoptosis following ischemia\/reperfusion injury - Chang_2017_Brain.Res_1677_118
Author(s) : Chang CF , Lai JH , Wu JC , Greig NH , Becker RE , Luo Y , Chen YH , Kang SJ , Chiang YH , Chen KY
Ref : Brain Research , 1677 :118 , 2017
Abstract : Stroke commonly leads to adult disability and death worldwide. Its major symptoms are spastic hemiplegia and discordant motion, consequent to neuronal cell death induced by brain vessel occlusion. Acetylcholinesterase (AChE) is upregulated and allied with inflammation and apoptosis after stroke. Recent studies suggest that AChE inhibition ameliorates ischemia-reperfusion injury and has neuroprotective properties. (-)-Phenserine, a reversible AChE inhibitor, has a broad range of actions independent of its AChE properties, including neuroprotective ones. However, its protective effects and detailed mechanism of action in the rat middle cerebral artery occlusion model (MCAO) remain to be elucidated. This study investigated the therapeutic effects of (-)-phenserine for stroke in the rat focal cerebral ischemia model and oxygen-glucose deprivation/reperfusion (OGD/RP) damage model in SH-SY5Y neuronal cultures. (-)-Phenserine mitigated OGD/PR-induced SH-SY5Y cell death, providing an inverted U-shaped dose-response relationship between concentration and survival. In MCAO challenged rats, (-)-phenserine reduced infarction volume, cell death and improved body asymmetry, a behavioral measure of stoke impact. In both cellular and animal studies, (-)-phenserine elevated brain-derived neurotrophic factor (BDNF) and B-cell lymphoma 2 (Bcl-2) levels, and decreased activated-caspase 3, amyloid precursor protein (APP) and glial fibrillary acidic protein (GFAP) expression, potentially mediated through the ERK-1/2 signaling pathway. These actions mitigated neuronal apoptosis in the stroke penumbra, and decreased matrix metallopeptidase-9 (MMP-9) expression. In synopsis, (-)-phenserine significantly reduced neuronal damage induced by ischemia/reperfusion injury in a rat model of MCAO and cellular model of OGD/RP, demonstrating that its anti-apoptotic/neuroprotective/neurotrophic cholinergic and non-cholinergic properties warrant further evaluation in conditions of brain injury.
ESTHER : Chang_2017_Brain.Res_1677_118
PubMedSearch : Chang_2017_Brain.Res_1677_118
PubMedID: 28963051

Title : A salicylate-based small molecule HS-Cm exhibits immunomodulatory effects and inhibits dipeptidyl peptidase-IV activity in human T cells - Liou_2014_Eur.J.Pharmacol_726C_124
Author(s) : Liou JT , Huang HS , Chiang ML , Lin CS , Yang SP , Ho LJ , Lai JH
Ref : European Journal of Pharmacology , 726C :124 , 2014
Abstract : Activated T cells are key players in chronic inflammatory diseases, including atherosclerosis. Salicylates, like aspirin, display not only anti-inflammatory, anti-thrombotic, anti-atherosclerotic activities, but also immunomodulatory effects in T cells at high dosages. Here, we aimed to identify potent immunomodulators for T cells through cell-based screening from a mini-library of 300 salicylate-based small molecules, and elucidate the mechanisms. Human peripheral blood T cells were isolated from buffy coat. Phorbol 12-myristate 13-acetate plus ionomycin (P/I) was used to stimulate T cells. Cytokine production was measured by enzyme-linked immunosorbent assays. T cell activation markers were determined by flow cytometry. The activation of transcription factors and kinases was analyzed by western blotting, electrophoretic mobility shift assay, or kinase assay. Through library screening, we identified a small molecule named HS-Cm [C13H9ClFNO2; N-(4-chloro-2-fluorophenyl)-2-hydroxybenzamide] that exhibited potent immunomodulatory effects on T cells with low cytotoxicity. In P/I-stimulated T cells, HS-Cm inhibited the production of interleukin-2, tumor necrosis factor-alpha, and interferon-gamma and suppressed the expression of surface activation markers CD25, CD69, and CD71, but not CD45RO. HS-Cm down-regulated DNA-binding activities of activator protein-1 and nuclear factor-kappa B, but not nuclear factor of activated T-cells, through inhibiting c-Jun N-terminal kinase/p38 and inhibitor of kappaB alpha (IkappaBalpha) kinase (IKK)/IkappaBalpha pathways, respectively. On the basis of structure-activity relationship, HS-Cm exerted considerable inhibition of dipeptidyl-peptidase IV/CD26 activity in T cells. Our results suggested that the small molecule HS-Cm exhibiting immunomodulatory effects on T cells may be useful for therapeutics in chronic inflammatory diseases, like atherosclerosis, diabetes and autoimmune arthritis.
ESTHER : Liou_2014_Eur.J.Pharmacol_726C_124
PubMedSearch : Liou_2014_Eur.J.Pharmacol_726C_124
PubMedID: 24491838

Title : A pan inhibitor of DASH family enzymes induces immunogenic modulation and sensitizes murine and human carcinoma cells to antigen-specific cytotoxic T lymphocyte killing: implications for combination therapy with cancer vaccines - Donahue_2014_Vaccine_32_3223
Author(s) : Donahue RN , Duncan BB , Fry TJ , Jones B , Bachovchin WW , Kiritsy CP , Lai JH , Wu W , Zhao P , Liu Y , Tsang KY , Hodge JW
Ref : Vaccine , :3223 , 2014
Abstract : Recent studies have suggested that pan inhibitors of dipeptidyl peptidase-4 activity and/or structure homologs (DASH), including ARI-4175, can mediate tumor regression by immune-mediated mechanisms. This study assessed the potential of combining ARI-4175 with cancer vaccines. We evaluated ARI-4175's effect on immunogenic modulation, ability to sensitize tumor cells to antigen-specific CTL killing, effect on immune-cell subsets and function, and antitumor activity in 2 tumor models, both as a monotherapy and in combination with a recombinant viral or dendritic cell (DC)-based tumor-cell vaccine. ARI-4175's effects on the growth, surface phenotype, and antigen-specific CTL-mediated lysis of murine and human carcinoma cell lines were assessed in vitro. In vivo, C57BL-6 mice were treated orally with ARI-4175, after which splenocytes were assessed by flow cytometry and functional assays. Antitumor studies were performed in murine models of colon carcinoma (MC38-CEA+ in CEA-transgenic C57BL-6 mice) and rhabdomyosarcoma (M3-9-M in C57BL-6 mice). Mice received oral ARI-4175 alone or in combination with a vaccine consisting of recombinant vaccinia/fowlpox CEA-TRICOM (colon model) or a DC-based tumor-cell vaccine (rhabdomyosarcoma model). Exposure to ARI-4175 had no effect on the proliferation or viability of carcinoma cells in vitro; however, it did alter tumor phenotype, making murine and human tumor cells more sensitive to antigen-specific CTL killing. Assessment of immune-cell subsets and function indicated that ARI-4175 increased levels of natural killer cells and DCs. Detrimental immune effects, including reduced T effector cells and increased immunosuppressive cells (Tregs, MDSCs), were normalized when treatment stopped, suggesting that scheduling is critical when combining this agent with vaccine. As a monotherapy, ARI-4175 had potent antitumor activity in both tumor models, and had even greater effects when combined with a vaccine (either DC-based or poxviral vector based). These findings provide the rationale for the combined use of cancer immunotherapy with DASH enzyme inhibitors such as ARI-4175.
ESTHER : Donahue_2014_Vaccine_32_3223
PubMedSearch : Donahue_2014_Vaccine_32_3223
PubMedID: 24731809

Title : A high-throughput, multiplexed assay for superfamily-wide profiling of enzyme activity - Bachovchin_2014_Nat.Chem.Biol_10_656
Author(s) : Bachovchin DA , Koblan LW , Wu W , Liu Y , Li Y , Zhao P , Woznica I , Shu Y , Lai JH , Poplawski SE , Kiritsy CP , Healey SE , DiMare M , Sanford DG , Munford RS , Bachovchin WW , Golub TR
Ref : Nat Chemical Biology , 10 :656 , 2014
Abstract : The selectivity of an enzyme inhibitor is a key determinant of its usefulness as a tool compound or its safety as a drug. Yet selectivity is never assessed comprehensively in the early stages of the drug discovery process, and only rarely in the later stages, because technical limitations prohibit doing otherwise. Here, we report EnPlex, an efficient, high-throughput method for simultaneously assessing inhibitor potency and specificity, and pilot its application to 96 serine hydrolases. EnPlex analysis of widely used serine hydrolase inhibitors revealed numerous previously unrecognized off-target interactions, some of which may help to explain previously confounding adverse effects. In addition, EnPlex screening of a hydrolase-directed library of boronic acid- and nitrile-containing compounds provided structure-activity relationships in both potency and selectivity dimensions from which lead candidates could be more effectively prioritized. Follow-up of a series of dipeptidyl peptidase 4 inhibitors showed that EnPlex indeed predicted efficacy and safety in animal models. These results demonstrate the feasibility and value of high-throughput, superfamily-wide selectivity profiling and suggest that such profiling can be incorporated into the earliest stages of drug discovery.
ESTHER : Bachovchin_2014_Nat.Chem.Biol_10_656
PubMedSearch : Bachovchin_2014_Nat.Chem.Biol_10_656
PubMedID: 24997602
Gene_locus related to this paper: human-PPME1

Title : Identification of selective and potent inhibitors of fibroblast activation protein and prolyl oligopeptidase - Poplawski_2013_J.Med.Chem_56_3467
Author(s) : Poplawski SE , Lai JH , Li Y , Jin Z , Liu Y , Wu W , Wu Y , Zhou Y , Sudmeier JL , Sanford DG , Bachovchin WW
Ref : Journal of Medicinal Chemistry , 56 :3467 , 2013
Abstract : Fibroblast activation protein (FAP) is a serine protease selectively expressed on reactive stromal fibroblasts of epithelial carcinomas. It is widely believed to play a role in tumor invasion and metastasis and therefore to represent a potential new drug target for cancer. Investigation into its biological function, however, has been hampered by the current unavailability of selective inhibitors. The challenge has been in identifying inhibitors that are selective for FAP over both the dipeptidyl peptidases (DPPs), with which it shares exopeptidase specificity, and prolyl oligopeptidase (PREP), with which it shares endopeptidase specificity. Here, we report the first potent FAP inhibitor with selectivity over both the DPPs and PREP, N-(pyridine-4-carbonyl)-d-Ala-boroPro (ARI-3099, 6). We also report a similarly potent and selective PREP inhibitor, N-(pyridine-3-carbonyl)-Val-boroPro (ARI-3531, 22). Both are boronic acid based inhibitors, demonstrating that high selectivity can be achieved using this electrophile. The inhibitors are stable, easy to synthesize, and should prove to be useful in helping to elucidate the biological functions of these two unique and interesting enzymes, as well as their potential as drug targets.
ESTHER : Poplawski_2013_J.Med.Chem_56_3467
PubMedSearch : Poplawski_2013_J.Med.Chem_56_3467
PubMedID: 23594271

Title : Quantitation of fibroblast activation protein (FAP)-specific protease activity in mouse, baboon and human fluids and organs - Keane_2013_FEBS.Open.Bio_4_43
Author(s) : Keane FM , Yao TW , Seelk S , Gall MG , Chowdhury S , Poplawski SE , Lai JH , Li Y , Wu W , Farrell P , Vieira de Ribeiro AJ , Osborne B , Yu DM , Seth D , Rahman K , Haber P , Topaloglu AK , Wang C , Thomson S , Hennessy A , Prins J , Twigg SM , McLennan SV , McCaughan GW , Bachovchin WW , Gorrell MD
Ref : FEBS Open Bio , 4 :43 , 2013
Abstract : The protease fibroblast activation protein (FAP) is a specific marker of activated mesenchymal cells in tumour stroma and fibrotic liver. A specific, reliable FAP enzyme assay has been lacking. FAP's unique and restricted cleavage of the post proline bond was exploited to generate a new specific substrate to quantify FAP enzyme activity. This sensitive assay detected no FAP activity in any tissue or fluid of FAP gene knockout mice, thus confirming assay specificity. Circulating FAP activity was approximately 20- and 1.3-fold less in baboon than in mouse and human plasma, respectively. Serum and plasma contained comparable FAP activity. In mice, the highest levels of FAP activity were in uterus, pancreas, submaxillary gland and skin, whereas the lowest levels were in brain, prostate, leukocytes and testis. Baboon organs high in FAP activity included skin, epididymis, bladder, colon, adipose tissue, nerve and tongue. FAP activity was greatly elevated in tumours and associated lymph nodes and in fungal-infected skin of unhealthy baboons. FAP activity was 14- to 18-fold greater in cirrhotic than in non-diseased human liver, and circulating FAP activity was almost doubled in alcoholic cirrhosis. Parallel DPP4 measurements concorded with the literature, except for the novel finding of high DPP4 activity in bile. The new FAP enzyme assay is the first to be thoroughly characterised and shows that FAP activity is measurable in most organs and at high levels in some. This new assay is a robust tool for specific quantitation of FAP enzyme activity in both preclinical and clinical samples, particularly liver fibrosis.
ESTHER : Keane_2013_FEBS.Open.Bio_4_43
PubMedSearch : Keane_2013_FEBS.Open.Bio_4_43
PubMedID: 24371721

Title : 4-Substituted boro-proline dipeptides: synthesis, characterization, and dipeptidyl peptidase IV, 8, and 9 activities - Wu_2012_Bioorg.Med.Chem.Lett_22_5536
Author(s) : Wu W , Liu Y , Milo LJ, Jr. , Shu Y , Zhao P , Li Y , Woznica I , Yu G , Sanford DG , Zhou Y , Poplawski SE , Connolly BA , Sudmeier JL , Bachovchin WW , Lai JH
Ref : Bioorganic & Medicinal Chemistry Lett , 22 :5536 , 2012
Abstract : The boroProline-based dipeptidyl boronic acids were among the first DPP-IV inhibitors identified, and remain the most potent known. We introduced various substitutions at the 4-position of the boroProline ring regioselectively and stereoselectively, and incorporated these aminoboronic acids into a series of 4-substituted boroPro-based dipeptides. Among these dipeptidyl boronic acids, Arg-(4S)-boroHyp (4q) was the most potent inhibitor of DPP-IV, DPP8 and DPP9, while (4S)-Hyp-(4R)-boroHyp (4o) exhibited the most selectivity for DPP-IV over DPP8 and DPP9.
ESTHER : Wu_2012_Bioorg.Med.Chem.Lett_22_5536
PubMedSearch : Wu_2012_Bioorg.Med.Chem.Lett_22_5536
PubMedID: 22853995

Title : Pro-soft Val-boroPro: a strategy for enhancing in vivo performance of boronic acid inhibitors of serine proteases - Poplawski_2011_J.Med.Chem_54_2022
Author(s) : Poplawski SE , Lai JH , Sanford DG , Sudmeier JL , Wu W , Bachovchin WW
Ref : Journal of Medicinal Chemistry , 54 :2022 , 2011
Abstract : Val-boroPro, 1, is a potent, but relatively nonspecific inhibitor of the prolyl peptidases. It has antihyperglycemic activity from inhibition of DPPIV but also striking anticancer activity and a toxicity for which the mechanisms are unknown. 1 cyclizes at physiological pH, which attenuates its inhibitory potency >100-fold, which is a "soft drug" effect. Here we show that this phenomenon can be exploited to create prodrugs with unique properties and potential for selective in vivo targeting. Enzyme-mediated release delivers 1 to the target in the active form at physiological pH; cyclization attenuates systemic pharmacological effects from subsequent diffusion. This "pro-soft" design is demonstrated with a construct activated by and targeted to DPPIV, including in vivo results showing improved antihyperglycemic activity and reduced toxicity relative to 1. Pro-soft derivatives of 1 can help to illuminate the mechanisms underlying the three biological activities, or to help localize 1 at a tumor and thereby lead to improved anticancer agents with reduced toxicity. The design concept can also be applied to a variety of other boronic acid inhibitors.
ESTHER : Poplawski_2011_J.Med.Chem_54_2022
PubMedSearch : Poplawski_2011_J.Med.Chem_54_2022
PubMedID: 21388136

Title : Dipeptide boronic acid inhibitors of dipeptidyl peptidase IV: determinants of potency and in vivo efficacy and safety - Connolly_2008_J.Med.Chem_51_6005
Author(s) : Connolly BA , Sanford DG , Chiluwal AK , Healey SE , Peters DE , Dimare MT , Wu W , Liu Y , Maw H , Zhou Y , Li Y , Jin Z , Sudmeier JL , Lai JH , Bachovchin WW
Ref : Journal of Medicinal Chemistry , 51 :6005 , 2008
Abstract : Dipeptidyl peptidase IV (DPP-IV; E.C., a serine protease that degrades the incretin hormones GLP-1 and GIP, is now a validated target for the treatment of type 2 diabetes. Dipeptide boronic acids, among the first, and still among the most potent DPP-IV inhibitors known, suffer from a concern over their safety. Here we evaluate the potency, in vivo efficacy, and safety of a selected set of these inhibitors. The adverse effects induced by boronic acid-based DPP-IV inhibitors are essentially limited to what has been observed previously for non-boronic acid inhibitors and attributed to cross-reactivity with DPP8/9. While consistent with the DPP8/9 hypothesis, they are also consistent with cross-reactivity with some other intracellular target. The results further show that the potency of simple dipeptide boronic acid-based inhibitors can be combined with selectivity against DPP8/9 in vivo to produce agents with a relatively wide therapeutic index (>500) in rodents.
ESTHER : Connolly_2008_J.Med.Chem_51_6005
PubMedSearch : Connolly_2008_J.Med.Chem_51_6005
PubMedID: 18783201

Title : Synthesis and characterization of constrained peptidomimetic dipeptidyl peptidase IV inhibitors: amino-lactam boroalanines - Lai_2007_J.Med.Chem_50_2391
Author(s) : Lai JH , Wu W , Zhou Y , Maw HH , Liu Y , Milo LJ, Jr. , Poplawski SE , Henry GD , Sudmeier JL , Sanford DG , Bachovchin WW
Ref : Journal of Medicinal Chemistry , 50 :2391 , 2007
Abstract : We describe here the epimerization-free synthesis and characterization of a new class of conformationally constrained lactam aminoboronic acid inhibitors of dipeptidyl peptidase IV (DPP IV; E.C. These compounds have the advantage that they cannot undergo the pH-dependent cyclization prevalent in most dipeptidyl boronic acids that attenuates their potency at physiological pH. For example, D-3-amino-1-[L-1-boronic-ethyl]-pyrrolidine-2-one (amino-D-lactam-L-boroAla), one of the best lactam inhibitors of DPP IV, is several orders of magnitude less potent than L-Ala-L-boroPro, as measured by Ki values (2.3 nM vs 30 pM, respectively). At physiological pH, however, it is actually more potent than L-Ala-L-boroPro, as measured by IC50 values (4.2 nM vs 1400 nM), owing to the absence of the potency-attenuating cyclization. In an interesting and at first sight surprising reversal of the relationship between stereochemistry and potency observed with the conformationally unrestrained Xaa-boroPro class of inhibitors, the L-L diastereomers of the lactams are orders of magnitude less effective than the D-L lactams. However, this interesting reversal and the unexpected potency of the D-L lactams as DPP IV inhibitors can be understood in structural terms, which is explained and discussed here.
ESTHER : Lai_2007_J.Med.Chem_50_2391
PubMedSearch : Lai_2007_J.Med.Chem_50_2391
PubMedID: 17458948