Bruton’s
tyrosine kinase (BTK), a non-receptor tyrosine
kinase, is a member of the Tec family of kinases and is essential
for B cell receptor (BCR) mediated signaling. BTK also plays a critical
role in the downstream signaling pathways for the Fcγ receptor
in monocytes, the Fcε receptor in granulocytes, and the RANK
receptor in osteoclasts. As a result, pharmacological inhibition of
BTK is anticipated to provide an effective strategy for the clinical
treatment of autoimmune diseases such as rheumatoid arthritis and
lupus. This article will outline the evolution of our strategy to
identify a covalent, irreversible inhibitor of BTK that has the intrinsic
potency, selectivity, and pharmacokinetic properties necessary to
provide a rapid rate of inactivation systemically following a very
low dose. With excellent in vivo efficacy and a very desirable tolerability
profile, 5a (branebrutinib, BMS-986195) has advanced
into clinical studies.
This report describes the biological activity, characterization, and SAR leading to 9d (BMS-754807) a small molecule IGF-1R kinase inhibitor in clinical development.
A search for structurally diversified
Tyk2 JH2 ligands from 6 (BMS-986165), a pyridazine carboxamide-derived
Tyk2 JH2
ligand as a clinical Tyk2 inhibitor currently in late development
for the treatment of psoriasis, began with a survey of six-membered
heteroaryl groups in place of the N-methyl triazolyl
moiety in 6. The X-ray co-crystal structure of an early
lead (12) revealed a potential new binding pocket. Exploration
of the new pocket resulted in two frontrunners for a clinical candidate.
The potential hydrogen bonding interaction with Thr599 in the pocket
was achieved with a tertiary amide moiety, confirmed by the X-ray
co-crystal structure of 29. When the diversity search
was extended to nicotinamides, a single fluorine atom addition was
found to significantly enhance the permeability, which directly led
to the discovery of 7 (BMS-986202) as a clinical Tyk2
inhibitor that binds to Tyk2 JH2. The preclinical studies of 7, including efficacy studies in mouse models of IL-23-driven
acanthosis, anti-CD40-induced colitis, and spontaneous lupus, will
also be presented.
Fluorine makes the difference: FIBX (see structure), the tetrafluoro derivative of the hypervalent iodine reagent, is more soluble and has higher reactivity than its nonfluorinated counterpart. An efficient synthesis of FIBX and initial reactions are presented. Some of these reactions can be conducted in standard organic solvents. Owing to the increased reactivity, new transformations and catalytic reactions may be possible.
Factor XIa (FXIa) is an enzyme in
the coagulation cascade thought
to amplify thrombin generation but has a limited role in hemostasis.
From preclinical models and human genetics, an inhibitor of FXIa has
the potential to be an antithrombotic agent with superior efficacy
and safety. Reversible and irreversible inhibitors of FXIa have demonstrated
excellent antithrombotic efficacy without increased bleeding time
in animal models (WeitzJ. I.ChanN. C.
Weitz, J. I.
Chan, N. C.
Arterioscler. Thromb.
Vasc. Biol.201939712).
Herein, we report the discovery of a novel series of macrocyclic FXIa
inhibitors containing a pyrazole P2′ moiety. Optimization of
the series for (pharmacokinetic) PK properties, free fraction, and
solubility resulted in the identification of milvexian (BMS-986177/JNJ-70033093, 17, FXIa K
i = 0.11 nM) as a clinical candidate for the
prevention and treatment of thromboembolic disorders, suitable for
oral administration.
Cyclopropanation of alkenes can be accomplished catalytically2 or stoichiometrically.3 Catalytic systems typically use a diazo reagent as the carbene source and a metal-containing mediator which forms a postulated metal carbene intermediate. Transfer of the carbene fragment from the metal to an alkene produces the cyclopropane product. Despite the wide variety of catalytic cyclopropanation systems, the putative carbene complex has never been isolated or observed in a catalytic system. This is somewhat surprising since the second category of cyclopropanation reactions involves the stoichiometric reaction of isolated car bene complexes with an alkene to form a cyclopropane. None of the isolated carbene complexes show catalytic cyclopropanation activity. Several years ago Callot demonstrated that rhodium porphyrins catalytically cyclopropanated a variety of alkenes in the presence of ethyl diazoacetate.4 Kodadek and co-workers have expanded this work and have attempted to prepare synthetically useful enantioselective catalysts for the formation of cyclopropanes.5 Their approach has been to use rhodium complexes with optically active porphyrins to induce chirality into the product. A similar approach was used for a variety of non-porphyrin copper catalysts.6 Kodadek has shown that the carbon-bound diazonium complex [(TTP)RhC(H)(C02Et)(N2W is an intermediate in the catalytic cyclopropanation of styrene with ethyl diazoacetate.7•8 In addition, kinetic studies suggest that the formation of a rhodium carbene complex is at least partially rate limiting.8 However, this carbene complex has not been isolated or directly observed. We report herein the use of osmium porphyrins as stereoselective cyclopropanation catalysts using ethyl diazoacetate with a variety of alkenes. In addition, our studies show that an isolable carbene complex ((TTP)Os=CHC02Et) is capable of catalytically and stoichiometrically cyclopropanating styrene.
Disciplines
Chemistry
CommentsReprinted ( (Figure 2). Likewise the B-e bonds are shorter than typical single bonds [1.558 A in B(C 2 H 3 h]. 13 Similar evidence has been offered to support delocalization of the two 1r electrons over the three-membered ring and aromatic character for the BC 2 ring in trimesitylborirene.12 Furthermore, the BC 2 rings in BC 2 H 2 and HBC 2 H 2 are seen to be virtually identical. Thus, the u radical site in BC 2 H 2 has no effect on the delocalized 1r bonding in the BC 2 ring. The photolysis of BC 2 H 2 in the near ultraviolet range indicates a strong absorption band in this region, in agreement with trimesitylborirene.13 The photolysis behavior also provides evidence for delocalized bonding as acetylene and ethylene absorb at shorter wavelengths.The appearance of BC 2 H 2 on diffusion and reaction of B atoms at 18 K in solid argon follows similar behavior for B0 2 • 1 These exothermic reactions proceed without activation energy. The BC 2 H 2 radical is the simplest borirene species yet observed and characterized. Further studies are in progress in this laboratory...
The somewhat systematic misreporting, on the part of the authors, of the MgCh and EDTA concentrations should be corrected for some of the nitrocellulose binding experiments. The concentrations of MgCL and EDTA in the standard incubation mixture used in experiments involving Fig- ures 2-4, 6, 7 and Table II were 0.5 mM for both components instead of 2 mM for MgCh and 0.1 mM for EDTA
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