James W. Leahy

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The phosphoinositide 3-kinases (PI3Ks) have been linked to an extraordinarily diversified group of cellular functions making these enzymes compelling targets for the treatment of disease. A large body of evidence has linked PI3Kγ to the modulation of autoimmune and inflammatory processes making it an intriguing target for drug discovery. Our high-throughput(More)
A series of novel, highly potent, selective, and ATP-competitive mammalian target of rapamycin (mTOR) inhibitors based on a benzoxazepine scaffold have been identified. Lead optimization resulted in the discovery of inhibitors with low nanomolar activity and greater than 1000-fold selectivity over the closely related PI3K kinases. Compound 28 (XL388)(More)
The potent, naturally occurring immunomodulators (-)-rapamycin (1) and (-)-27-demethoxyrapamycin (2) have been synthesized via a unified and highly convergent strategy. In the preceding paper we discussed the construction of common building blocks A-C and their linkage to provide the C(21-42) segments of 1 and 2. Herein we describe model studies of triene(More)
We have synthesized and evaluated a series of tetramic acid-based and hydroxyquinolinone-based inhibitors of plasminogen activator inhibitor-1 (PAI-1). These studies resulted in the identification of several compounds which showed excellent potency against PAI-1. The design, synthesis and SAR of these compounds are described.
We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors. Advanced lead 10d demonstrated a significant(More)
A series of subtype selective sphingosine 1-phosphate receptor 1 (S1P(1)) antagonists are disclosed. Our high-throughput screening campaign revealed hit 1 for which an increase in potency and mouse oral exposure was achieved with minor modifications to the chemical scaffold. In vivo efficacy revealed that at high doses compounds 12 and 15 inhibited tumor(More)
Agmatine N-acetyltransferase (AgmNAT) catalyzes the formation of N-acetylagmatine from acetyl-CoA and agmatine. Herein, we provide evidence that Drosophila melanogaster AgmNAT (CG15766) catalyzes the formation of N-acetylagmatine using an ordered sequential mechanism; acetyl-CoA binds prior to agmatine to generate an AgmNAT•acetyl-CoA•agmatine ternary(More)
We have determined that tetrahydroindazoles such as 1 show potent activity against Leishmania donovani, the causative agent of leishmaniasis. While the Hsp90 activity and anticancer properties of 1 have previously been explored, we present here our efforts to optimize their activity against L. donovani via the synthesis of novel analogues designed to probe(More)
The convergent, highly enantioselective synthesis of rhizoxin D, a natural product possessing potent antitumor and antifungal bioactivity, is described. The C(1)-C(9) fragment of the molecule was synthesized utilizing a threefold pseudosymmetric intermediate ultimately derived from gamma-butyrolactone. The central core of rhizoxin D was prepared via a(More)
Peptidylglycine α-amidating monooxygenase (PAM) is a bifunctional enzyme that catalyzes the final reaction in the maturation of α-amidated peptide hormones. Peptidylglycine α-hydroxylating monooxygenase (PHM) is the PAM domain responsible for the copper-, ascorbate- and O2-dependent hydroxylation of a glycine-extended peptide. Peptidylamidoglycolate lyase(More)