Obesity and type II diabetes are closely linked metabolic syndromes that afflict >100 million people worldwide. Although protein tyrosine phosphatase 1B (PTP1B) has emerged as a promising target for the treatment of both syndromes, the discovery of pharmaceutically acceptable inhibitors that bind at the active site remains a substantial challenge. Here we describe the discovery of an allosteric site in PTP1B. Crystal structures of PTP1B in complex with allosteric inhibitors reveal a novel site located approximately 20 A from the catalytic site. We show that allosteric inhibitors prevent formation of the active form of the enzyme by blocking mobility of the catalytic loop, thereby exploiting a general mechanism used by tyrosine phosphatases. Notably, these inhibitors exhibit selectivity for PTP1B and enhance insulin signaling in cells. Allosteric inhibition is a promising strategy for targeting PTP1B and constitutes a mechanism that may be applicable to other tyrosine phosphatases.

The synthesis and structure-activity relationship study of a series of compounds with heterocycles in place of the cis double bond in combretastatin A-4 (CA-4) are described. Substituted tosylmethyl isocyanides were found to be the key intermediates in construction of the heterocycles. Cytotoxicities of the heterocycle-based CA-4 analogues were evaluated against NCI-H460 and HCT-15 cancer cell lines. 3-Amino-4-methoxyphenyl and N-methyl-indol-5-yl were the best replacements for the 3-hydroxy-4-methoxyphenyl in CA-4. 4,5-Disubstituted imidazole was found to be the best for the replacement of the cis double bond in CA-4. Medicinal chemistry efforts led to the discovery of compounds 24h and 25f that were found to be 32 and 82% bioavailable, respectively, in rat. Evaluation of 24h and 25f against murine M5076 reticulum sarcoma in mice revealed that both compounds were orally efficacious with an increase in life span of 38.5 and 40.5%, respectively.

Inhibition of mutant IDH1 is being evaluated clinically as a treatment option for oncology. Here we describe the structure-based design and optimization of quinoline lead compounds to identify FT-2102, a potent, orally bioavailable, brain penetrant, and selective mIDH1 inhibitor. FT-2102 has excellent ADME/PK properties and reduces 2-hydroxyglutarate levels in an mIDH1 xenograft tumor model. This compound has been selected as a candidate for clinical development in hematologic malignancies, solid tumors, and gliomas with mIDH1.

LFA-1/ICAM-1 interaction is essential in support of inflammatory and specific T-cell regulated immune responses by mediating cell adhesion, leukocyte extravasation, migration, antigen presentation, formation of immunological synapse, and augmentation of T-cell receptor signaling. The increase of ICAM-1 expression levels in conjunctival epithelial cells and acinar cells was observed in animal models and patients diagnosed with dry eye. Therefore, it has been hypothesized that small molecule LFA-1/ICAM-1 antagonists could be an effective topical treatment for dry eye. In this letter, we describe the discovery of a potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonist (SAR 1118) and its development as an ophthalmic solution for treating dry eye.

Mutations at the arginine residue (R132) in isocitrate dehydrogenase 1 (IDH1) are frequently identified in various human cancers. Inhibition of mutant IDH1 (mIDH1) with small molecules has been clinically validated as a promising therapeutic treatment for acute myeloid leukemia and multiple solid tumors. Herein, we report the discovery and optimization of a series of quinolinones to provide potent and orally bioavailable mIDH1 inhibitors with selectivity over wild-type IDH1. The X-ray structure of an early lead 24 in complex with mIDH1-R132H shows that the inhibitor unexpectedly binds to an allosteric site. Efforts to improve the in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) properties of 24 yielded a preclinical candidate 63. The detailed preclinical ADME and pharmacology studies of 63 support further development of quinolinone-based mIDH1 inhibitors as therapeutic agents in human trials.

Because the vinylogous Mannich reaction of substituted furans with iminium ions is a useful construction in alkaloid synthesis, it is important to know what effects substituents on the two reacting partners have upon the stereoselectivity of the reaction. Toward this end, the additions of the methylated furans 9a − h to the iminium ion generated in situ from the ethoxy carbamate 10 were examined. Generally, mixtures (3−24:1) of the threo and erythro adducts 11a − h and 12a − h were obtained in 50−96% combined yields, with the threo isomers being the major products. Two extraordinarily concise asymmetric syntheses of (+)-croomine (1) have been completed using a novel strategy, highlighted by two vinylogous Mannich reactions as key constructions. The first such reaction involved the addition of 5-(4-bromobut-1-yl)-3-methyl-2-(triisopropylsilyloxy)furan to the N-acyliminium salt derived from the l-pyroglutamic acid derivative 17 to give the adduct [5(S),2‘(S),5‘(S)]-5-(4‘ ‘-bromobut-1‘ ‘yl)-5-[N-(tert-butoxycarbonyl)-2‘-(methoxycarbonyl)-pyrrolidin-5‘-yl]-3-methyl-2(5H)-furanone (18) as the major product. Refunctionalization of 18 led to the tricyclic intermediate [3‘S-[3‘α,9‘α(S*),9‘aα]]-decahydro-4-methyl-5-oxospiro[furan-2(3H),9‘-[9H]pyrrolo[1,2-a]azepin]-3‘-carboxylic acid, hydrobromide salt, which was, in turn, converted to an iminium salt that underwent a second vinylogous Mannich reaction to give [3‘S-[3‘α(R*),9‘α(S*),9‘aα]]-3‘-(2,5-dihydro-4-methyl-5-oxo-2-furanyl)decahydro-4-methylspiro[furan-2(5H),9‘-[9H]pyrrolo[1,2-a]azepin-5-one (24) as the major adduct. Stereoselective reduction of the unsaturated lactone 24 gave 1, completing a synthesis that required a total of only 11 chemical steps from commercially available starting materials. In a second approach, the initial Mannich adduct [5(S),2‘(S),5‘(S)]-5-(4‘ ‘-bromobut-1‘ ‘-yl)-5-[2‘-(methoxycarbonyl)pyrrolidin-5‘-yl]-3-methyl-2(5H)-furanone was transformed into the unsaturated tricyclic intermediate [3‘S-[3‘α(R*),9‘α(S*),9‘aα]]-3‘-(2,5-dihydro-4-methyl-5-oxo-2-furanyl)-1‘,2‘,3‘,5‘,6‘,7‘,8‘-octahydro-4-methylspiro[furan-2(5H),9‘-[9H]pyrrolo[1,2-a]azepin]-5-one, which underwent hydrogenation to give 1 as the only isolable product, thereby completing a synthesis that required only 10 steps.

The alkaloid-rich extracts obtained from plants belonging to the Stemonaceae family (Stemona and Croomia species) have been used in traditional Chinese folk medicine to prepare herbal teas for treating numerous disorders, including pertussis, pulmonary tuberculosis, and bronchitis; several alkaloids also exhibit insecticidal activity. 1 Although this class of alkaloids is relatively small, there is an increasing interest in representative members of the family owing to their unique and complex structures coupled with the rich opportunities for developing new chemistry for their synthesis. 2 As illustrated by the prototypical examples croomine (1) and stemonine (2), these novel polycyclic alkaloids incorporate a butyrolactone ring that is appended or annelated to a 1-azabicyclo[5.3.0]decane nucleus.We have recently investigated the vinylogous Mannich reaction as a key construction for the synthesis of alkaloid natural products. 3 The general plan is illustrated by the nucleophilic addition of the 2-trialkylsilyloxy furan 4 to the cyclic iminium ion 3 to provide a mixture of the isomeric adducts threo-5 and erythro-5 in which the threo-5 product typically dominates (eq 1). 3a,4 Since the stereochemistry at the newly created stereogenic centers in the threo-5 adduct corresponds to the pairwise relationships at C(9)-C(9a) and C(3)-C(14) of croomine (1), it occurred to us that vinylogous Mannich reactions might be applied to the design of a highly convergent strategy for the synthesis of 1 and related alkaloids. In such an approach to 1, both the A and D rings would be appended by sequential addition of substituted silyloxy furan subunits to the pyrrolidine core C, thereby forming bonds a and c. The sevenmembered B ring would be constructed via intramolecular N-alkylation to make bond b. We now report the successful implementation of this strategy in an extraordinarily concise, asymmetric synthesis of (+)-croomine (1).The synthesis commenced with the reaction of commercially available 3-methyl-2-(5H)-furanone (6) (Scheme 1) with triisopropylsilyl triflate (TIPS-OTf) in the presence of triethylamine to give the (trialkylsilyl)oxy furan 7 in 99% yield. 5,6 The furan 7 is destined to be incorporated as both the A and D rings of the target 1. Metallation of 7 followed by alkylation with 1,4-(1) For leading references to structural and biological investigations of the Stemona alkaloids, see: (a) Koyanma, H.; Oda, K. J. Chem. Soc. B 1970, 268. (b) Lizuka, H.; Irie, H.; Masaki, N.; Osaki, K.; Uyeo, S. Sano, M.; Ishii, A. I.; Kino, H.; Fukushima, S.; Noro, T. The structure assigned to each compound is in full accord with its spectral ( 1 H and 13 C NMR, IR, mass) characteristics; molecular composition of new compounds was established by high resolution mass measurements of purified materials. All yields are based on isolated, purified material judged >95% pure by 1 H NMR spectroscopy; the structures of compounds 10, 11, 15, and 16 were determined by X-ray crystallography. Scheme 13299

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